203 results on '"Cosconati, S."'
Search Results
2. Design, synthesis and biological evaluation of novel rhodesain inhibitors for the treatment of Human African Trypanosomiasis
- Author
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Maiorana, S., Ettari, R., Previti, S., Cosconati, S., and Zappalà, M.
- Published
- 2019
3. Expanding the quinazoline ring to 3H-benzo[e][1,4]diazepine: development of new and selective G9a inhibitors
- Author
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Milite, C., Feoli, A., Rescigno, Donatella, Pisapia, Vincenzo, Cosconati, S., Castellano, S., and Sbardella, G.
- Published
- 2018
4. High-throughput drug screening by Printing Biology
- Author
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Arrabito, Giuseppe Domenico, Cavaleri, Felicia, VETRI, Valeria, MILITELLO, Valeria, Di Maro S., Cosconati S., Novellino E., LEONE, Maurizio, PIGNATARO, Bruno Giuseppe, Arrabito G., Cavaleri F., Vetri V., Militello V., Di Maro S., Cosconati S., Novellino E., Leone M., and Pignataro B.
- Subjects
Printing Biology, Inkjet printing, Raster Image Correlation Spectroscopy - Abstract
Printing biology is our way to define a novel field employing material printing techniques generally used in plastic electronics to solve important issues of biology by miniaturized and high-throughput platforms. In this field, we already showed the possibility to use Dip Pen Lithography to fabricate single-cell biochips [1]. Also,we employed non-contact patterning methods such as inkjet printing methods to fabricate microarrays for drug screening at solid-liquid interfaces [2] or in picoliter-scale liquid droplets [3] so enabling high-throughput screening of chemical libraries onto disease-based targets. In this regard, printing methods would greatly reduce times and costs of standard drug screening campaigns which are commonly based on complex liquid handling robotics and are time and reagent consuming (micro-, nanoliter scale). In this work, we show a low-cost, general and miniaturized printing biology approach for drug screening, by combining Inkjet Printing and Dip Pen Lithography to develop the biochip. We show the possibility to precisely deliver femtoliter scale droplets of protein targets by Dip Pen Lithography by finely tuning the deposition parameters and ink formulation. Protein solutions are spiked with glycerol at 30 % v/v and are deposited at defined values of humidity (50 % -70 % R.H.). This permits to obtain microscale droplet arrays where picoliter volumes of drug candidates solutions are readily deposited by inkjet printing. In this way, it is possible to produce different drug targets concentration directly on-chip. Fluorescence confocal microscopy is here used to quantify drug-ligand interaction by means of standard intensity based imaging and fluctuation techniques that permit mapping concentration and important biophysical parameters including diffusion coefficients of fluorolabeled (or intrinsically fluorescent) ligands at nanomolar concentration. Outputs obtained on different systems by means of such a miniaturized approach are compared with the ones obtained on standard microliters volumes samples, confirming the ability of our biochip printing methodology to discriminate ligand-target interactions in different compounds. MiUR and the PRIN2012 program are acknowledged for fudings.
- Published
- 2015
5. Development of novel 1,4-benzodiazepines as antitrypanosomal agents
- Author
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Previti, Santo, Ettari, Roberta, Maiorana, Santina, Cosconati, S., Schirmeister, T., Grasso, Silvana, and Zappala', Maria
- Published
- 2016
6. Development of novel indole-based tdp1 inhibitors for anticancer therapy
- Author
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Robello, Marco, Barresi, Elisabetta, Taliani, Sabrina, Simorini, Francesca, Cosconati, S., Di Leva, F. S., Marchand, C., Pommier, Y., Di Santo, R., Novellino, E., and DA SETTIMO PASSETTI, Federico
- Published
- 2016
7. Water-Soluble Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines as Human A(3) Adenosine Receptor Antagonists
- Author
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Baraldi PG, Saponaro G, Romagnoli R, Aghazadeh Tabrizi M, Baraldi S, Moorman AR, Cosconati S, Gessi S, Merighi S, Varani K, Borea PA, Preti D., DI MARO, SALVATORE, MARINELLI, LUCIANA, NOVELLINO, ETTORE, Baraldi, Pg, Saponaro, G, Romagnoli, R, Aghazadeh Tabrizi, M, Baraldi, S, Moorman, Ar, Cosconati, S, DI MARO, Salvatore, Marinelli, Luciana, Gessi, S, Merighi, S, Varani, K, Borea, Pa, Preti, D., Novellino, Ettore, Cosconati, Sandro, and Marinelli, L
- Subjects
Aqueous solution ,Pyrimidine ,Molecular model ,Chemistry ,Stereochemistry ,Medicinal chemistry ,Adenosine receptor ,chemistry.chemical_compound ,Water soluble ,Drug Discovery ,Molecular Medicine ,Moiety ,Solubility ,IC50 - Abstract
A relevant problem of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C 5 position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH ( 515, IC 50(hA 2B) > 5 μM) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands. © 2012 American Chemical Society.
- Published
- 2012
8. Pursuing Aldose Reductase Inhibitors through in Situ Cross-Docking and Similarity-Based Virtual Screening
- Author
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Cosconati S., La Motta C., Sartini S., Da Settimo F., Olson A. J., MARINELLI, LUCIANA, NOVELLINO, ETTORE, Cosconati, S., Marinelli, Luciana, La Motta, C., Sartini, S., Da Settimo, F., Olson, A. J., and Novellino, Ettore
- Published
- 2009
9. Identification of anxiolytic/non sedative agents among indol-3-ylglyoxylamides acting as functionally selective agonists at the GABAA alfa2 benzodiazepine receptor
- Author
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Taliani S., Da Settimo F., Marini A. M., La Motta C., Simorini F., Salerno S., Cosconati S., Salvetti F., L’Abbate G., Trasciatti S., Montali M., Costa B., Martini C., COSIMELLI, BARBARA, NOVELLINO, ETTORE, GRECO, GIOVANNI, MARINELLI, LUCIANA, Taliani, S., Cosimelli, Barbara, Da Settimo, F., Marini, A. M., La Motta, C., Simorini, F., Salerno, S., Novellino, Ettore, Greco, Giovanni, Cosconati, S., Marinelli, Luciana, Salvetti, F., L’Abbate, G., Trasciatti, S., Montali, M., Costa, B., and Martini, C.
- Published
- 2009
10. Phenylpyrazolo[1,5-a]quinazolin-5(4H)-one: a suitable scaffold for the development of noncamptothecin Topoisomerase I (top1) inhibitors
- Author
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Pugliesi, I., Barresi, Elisabetta, Taliani, Sabrina, Salerno, Silvia, Marchand, C., Agama, K., Simorini, Francesca, LA MOTTA, Concettina, Marini, ANNA MARIA, Pommier, Y., Di Leva, F. S., Di Santo, R., Cosconati, S., Novellino, E., and DA SETTIMO PASSETTI, Federico
- Published
- 2013
11. Benzoxadiazole Derivatives: Atypical Inhibitors of Aldose Reductase
- Author
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Sartini, S., Cosconati, S., Barresi, E., Salerno, Silvia, Simorini, Francesca, Taliani, Sabrina, Pietra, La, Marinelli, V., LA MOTTA, Concettina, Marini, ANNA MARIA, DA SETTIMO PASSETTI, Federico, and Novellino, F.
- Published
- 2011
12. Novel Pyrazolopyrimidine Derivatives as Therapeutic Agents for the Treatment of Medullary Thyroid Carcinoma
- Author
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Sartini, S., Morelli, M., Patti, A., Simorini, Francesca, Taliani, Sabrina, Salerno, Silvia, Marini, ANNA MARIA, Cosconati, S., La Pietra, V., Marinelli, L., Fioravanti, A., Di Desidero, T., Bocci, Guido, Ferrari, S. M., Fallahi, P., Antonelli, A., LA MOTTA, Concettina, DA SETTIMO PASSETTI, Federico, and Novellino, E.
- Published
- 2011
13. Lead optimization of a novel molecular scaffold in search for novel MMP-13 inhibitors
- Author
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Taliani, Sabrina, Pugliesi, I., Barresi, Elisabetta, Simorini, Francesca, Salerno, Silvia, LA MOTTA, Concettina, Marini, ANNA MARIA, Nuti, Elisa, La Pietra, V., Cosconati, S., Marinelli, L., Rossello, Armando, DA SETTIMO PASSETTI, Federico, and Novellino, E.
- Published
- 2010
14. Inhibition of Ocular Aldose Reductase by a New Benzofuroxane Derivative Ameliorates Rat Endotoxic Uveitis
- Author
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Di Filippo, C., primary, Zippo, M. V., additional, Maisto, R., additional, Trotta, M. C., additional, Siniscalco, D., additional, Ferraro, B., additional, Ferraraccio, F., additional, La Motta, C., additional, Sartini, S., additional, Cosconati, S., additional, Novellino, E., additional, Gesualdo, C., additional, Simonelli, F., additional, Rossi, S., additional, and D’Amico, M., additional
- Published
- 2014
- Full Text
- View/download PDF
15. Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4.
- Author
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Demmer, O., Dijkgraaf, I., Schumacher, U., Marinelli, L., Cosconati, S., Gourni, E., Wester, H.J., Kessler, H., Demmer, O., Dijkgraaf, I., Schumacher, U., Marinelli, L., Cosconati, S., Gourni, E., Wester, H.J., and Kessler, H.
- Abstract
Item does not contain fulltext, The chemokine receptor CXCR4 is a critical regulator of inflammation and immune surveillance, and it is specifically implicated in cancer metastasis and HIV-1 infection. On the basis of the observation that several of the known antagonists remarkably share a C(2) symmetry element, we constructed symmetric dimers with excellent antagonistic activity using a derivative of a cyclic pentapeptide as monomer. To optimize the binding affinity, we investigated the influence of the distance between the monomers and the pharmacophoric sites in the synthesized constructs. The affinity studies in combination with docking computations support a two-site binding model. In a final step, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was introduced as chelator for (radio-)metals, thus allowing to exploit these compounds as a new group of CXCR4-binding peptidic probes for molecular imaging and endoradiotherapeutic purposes. Both the DOTA conjugates and some of their corresponding metal complexes retain good CXCR4 affinity, and one (68)Ga labeled compound was studied as PET tracer.
- Published
- 2011
16. Increasing avß3 selectivity of the anti-angiogenic drug cilengitide by N-methylation
- Author
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Universitat Politècnica de Catalunya. Departament de Ciència dels Materials i Enginyeria Metal·lúrgica, Mas Moruno, Carlos, Beck, J.G., Doedens, L., Frank, A.O., Marinelli, L., Cosconati, S., Novellino, E., Kessler, H., Universitat Politècnica de Catalunya. Departament de Ciència dels Materials i Enginyeria Metal·lúrgica, Mas Moruno, Carlos, Beck, J.G., Doedens, L., Frank, A.O., Marinelli, L., Cosconati, S., Novellino, E., and Kessler, H.
- Abstract
Thumbnail image of graphical abstract A subtle change: Structural changes upon amide bond methylation improve the selectivity of the anti-angiogenic drug Cilengitide, which after N-methylation at distinct positions discriminates between the closely related pro-angiogenic integrins avß3 and avß5 (see scheme)., Peer Reviewed, Postprint (published version)
- Published
- 2011
17. Conformational control of integrin subtype selectivity in isoDGR peptide motifs: A biological switch
- Author
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Universitat Politècnica de Catalunya. Departament de Ciència dels Materials i Enginyeria Metal·lúrgica, Frank, A.O., Otto, E., Mas Moruno, Carlos, Schiller, H., Marinelli, L., Cosconati, S., Bochen, A., Vossmeyer, D., Zahn, G., Stragies, R., Novellino, E., Kessler, H., Universitat Politècnica de Catalunya. Departament de Ciència dels Materials i Enginyeria Metal·lúrgica, Frank, A.O., Otto, E., Mas Moruno, Carlos, Schiller, H., Marinelli, L., Cosconati, S., Bochen, A., Vossmeyer, D., Zahn, G., Stragies, R., Novellino, E., and Kessler, H.
- Abstract
Thumbnail image of graphical abstract The rearrangement of asparagine to isoaspartate (isoD) is responsible for the deactivation of many functional proteins. However, the isoDGR motif, which is optimally presented as a conformationally controlled cyclic pentapeptide, binds selectively to a5ß1 integrin (see the docking model) with an affinity comparable to that of the peptidic antitumor agent Cilengitide, Peer Reviewed, Postprint (published version)
- Published
- 2010
18. NMR solution structure of the 4:1 complex between an uncharged distamycin A analogue and [d(TGGGGT)]4
- Author
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Cosconati, S., primary, Marinelli, L., additional, Trotta, R., additional, Virno, A., additional, De Tito, S., additional, Romagnoli, R., additional, Pagano, B., additional, Limongelli, V., additional, Giancola, C., additional, Baraldi, P., additional, Mayol, L., additional, Novellino, E., additional, and Randazzo, A., additional
- Published
- 2010
- Full Text
- View/download PDF
19. Architecture of the Human Urotensin II Receptor: Comparison of the Binding Domains of Peptide and Non-Peptide Urotensin II Agonists
- Author
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Lavecchia, A., Cosconati, S., and Novellino, E.
- Abstract
The human urotensin II receptor (h-UTR) is a member of the family of rhodopsin-like G-protein-coupled receptors (GPCRs) involved in the modulation of the functionality of many tissues and organs. Recently the urotensin-II (UII) neuropeptide, which is a potent vasoconstrictor in mammals and it is postulated to play a central role in cardiovascular homeostasis, has been identified as an agonist of the UII receptor. To elucidate the receptor's molecular recognition, a h-UTR model was constructed by homology modeling using the 2.6 Å crystal structure of bovine rhodopsin as a template and subsequently refined by molecular dynamics simulations. The molecular recognition of h-UTR was probed by automated docking of P5U, a potent UII peptide agonist, as well as of the non-peptide compounds
1 − 4 . We believe that this new model of the h-UTR provides the means for understanding the ligand's potency and for facilitating the design of novel and more potent UII ligands.- Published
- 2005
20. High-throughput screening at the picoliter scale by combining Dip Pen Lithography with Inkjet printing
- Author
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Arrabito, Giuseppe Domenico, CAVALERI, FELICIA, VETRI, Valeria, Di Maro, S, Cosconati, S, Novellino, E, PELLERITO, Claudia, MILITELLO, Valeria, LEONE, Maurizio, PIGNATARO, Bruno Giuseppe, Arrabito, G, Cavaleri, F, Vetri, V, Di Maro, S, Cosconati, S, Novellino, E, Pellerito, C, Militello, V, Leone, M, and Pignataro, B
- Subjects
Inkjet printing, drug screening, drug screening - Abstract
Drug screening is a complex, expensive and time consuming field consisting of diseasebased target identification in conjunction with high-throughput screening of chemical and natural product libraries. Conventional drug screening technology is usually time and reagent consuming (micro-, nanoliter scale) and is based on complex liquid handling robotics. In this work, we show a low-cost and miniaturized drug screening methodology based on direct bio-printing methodologies like Inkjet Printing and Dip Pen Lithography. We show the possibility to precisely deliver femtoliter scale droplets of protein targets by Dip Pen Lithography by finely tuning deposition parameters. This allows obtaining microscale droplet arrays where picoliter volumes of drug candidates solutions are readily deposited by inkjet printing. Exact and accurate pattern alignment is shown. Modulation of deposition procedure allows producing gradients of drug target concentration directly on-chip. A fluorescence confocal microscope is used to quantify drug-ligand interaction by means of standard intensity based imaging and fluctuation techniques which allows mapping concentration and diffusion coefficients of fluorolabeled ligands at nanomolar concentration. Outputs obtained on different systems by means of this new method are compared with the ones obtained by established microliters volumes samples, confirming the ability of our “chip printing” technique to discriminate ligand-target interactions for different compounds.
21. Translocator protein (tspo) ligand residence time: a new parameter to predict neurosteroidogenic efficacy for n,n-dialkyl-2-arylindol-3-ylglyoxylamides (PIGAs)
- Author
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SABRINA TALIANI, BARBARA COSTA, Cosconati, S., Elisabetta Barresi, Eleonora Da Pozzo, Bruno, A., Marco Robello, Silvia Salerno, Simorini, Francesca, Novellino, E., FEDERICO DA SETTIMO PASSETTI, and Claudia Martini
22. Olive Leaves and Hibiscus Flowers Extracts-Based Preparation Protect Brain from Oxidative Stress-Induced Injury
- Author
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Ettore Novellino, Matteo Micucci, Sandro Cosconati, Maria Frosini, Alberto Chiarini, Elda Chiaino, Roberta Budriesi, Chiaino, E., Micucci, M., Cosconati, S., Novellino, E., Budriesi, R., Chiarini, A., Frosini, M., Chiaino E., Micucci M., Cosconati S., Novellino E., Budriesi R., Chiarini A., and Frosini M.
- Subjects
0301 basic medicine ,Antioxidant ,Hybiscus sabdariffa (L.) ,Olea europea (L.) ,excitotoxicity ,natural compounds ,neurodegenerative diseases ,neuroprotection ,oxidative stress ,Physiology ,medicine.medical_treatment ,Clinical Biochemistry ,Excitotoxicity ,Natural compounds ,Neurodegenerative diseases ,Neuroprotection ,Oxidative stress ,Natural compound ,Pharmacology ,Neurodegenerative disease ,medicine.disease_cause ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,Nutraceutical ,medicine ,Molecular Biology ,biology ,Chemistry ,Hibiscus sabdariffa ,lcsh:RM1-950 ,Cell Biology ,Hibiscus ,biology.organism_classification ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Olea ,030220 oncology & carcinogenesis - Abstract
Oxidative stress (OS) arising from tissue redox imbalance, critically contributes to the development of neurodegenerative disorders. Thus, natural compounds, owing to their antioxidant properties, have promising therapeutic potential. Pres phytum (PRES) is a nutraceutical product composed of leaves- and flowers-extracts of Olea europaea L. and Hibiscus sabdariffa L., respectively, the composition of which has been characterized by HPLC coupled to a UV-Vis and QqQ-Ms detector. As PRES possess antioxidant, antiapoptotic and anti-inflammatory properties, the aim of this study was to assess its neuroprotective effects in human neuroblastoma SH-SY5Y cells and in rat brain slices subjected to OS. PRES (1&ndash, 50 µ, g/mL) reverted the decrease in viability as well as the increase in sub-diploid-, DAPI-and annexin V-positive-cells, reduced ROS formation, recovered the mitochondrial potential and caspase-3 and 9 activity changes caused by OS. PRES (50&ndash, 100 µ, g/mL) neuroprotective effects occurred also in rat brain slices subjected to H2O2 challenge. Finally, as the neuroprotective potential of PRES is strictly related to its penetration into the brain and a relatively good pharmacokinetic profile, an in-silico prediction of its components drug-like properties was carried out. The present results suggest the possibility of PRES as a nutraceutical, which could help in preventing neurodegenerative diseases.
- Published
- 2020
23. FEPrepare: A Web-Based Tool for Automating the Setup of Relative Binding Free Energy Calculations
- Author
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Dimitris Dellis, Zoe Cournia, Sandro Cosconati, Giorgio Amendola, Stamatia Zavitsanou, Alexios Chatzigoulas, Michail Papadourakis, Alexandros Tsengenes, Zavitsanou, S., Tsengenes, A., Papadourakis, M., Amendola, G., Chatzigoulas, A., Dellis, D., Cosconati, S., and Cournia, Z.
- Subjects
Scheme (programming language) ,Binding free energy ,Computer science ,Entropy ,General Chemical Engineering ,Molecular Dynamics Simulation ,Library and Information Sciences ,01 natural sciences ,Force field (chemistry) ,Computational science ,Physical Phenomena ,Set (abstract data type) ,03 medical and health sciences ,0103 physical sciences ,Web application ,Topology (chemistry) ,030304 developmental biology ,computer.programming_language ,Internet ,0303 health sciences ,010304 chemical physics ,business.industry ,General Chemistry ,Computer Science Applications ,Thermodynamics ,business ,computer ,Energy (signal processing) - Abstract
Relative binding free energy calculations in drug design are becoming a useful tool in facilitating lead binding affinity optimization in a cost- and time-efficient manner. However, they have been limited by technical challenges such as the manual creation of large numbers of input files to set up, run, and analyze free energy simulations. In this Application Note, we describe FEPrepare, a novel web-based tool, which automates the setup procedure for relative binding FEP calculations for the dual-topology scheme of NAMD, one of the major MD engines, using OPLS-AA force field topology and parameter files. FEPrepare provides the user with all necessary files needed to run a FEP/MD simulation with NAMD. FEPrepare can be accessed and used at https://feprepare.vi-seem.eu/.
- Published
- 2021
24. Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase
- Author
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Nicole Grandi, Enzo Tramontano, Francesca Esposito, Davide Ialongo, Alessandro De Leo, Giorgio Amendola, Daniela De Vita, Antonella Messore, Valentina Noemi Madia, Marie-Line Andreola, Ettore Novellino, Mathieu Métifiot, Sandro Cosconati, Roberta Costi, Angela Corona, Roberto Di Santo, Valeria Tudino, Francesco Saccoliti, Luigi Scipione, Microbiologie Fondamentale et Pathogénicité [Bordeaux] (MFP), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Messore, A., Corona, A., Madia, V. N., Saccoliti, F., Tudino, V., De Leo, A., Ialongo, D., Scipione, L., De Vita, D., Amendola, G., Novellino, E., Cosconati, S., Metifiot, M., Andreola, M. -L., Esposito, F., Grandi, N., Tramontano, E., Costi, R., and Di Santo, R.
- Subjects
Quinolone ,Anti-HIV Agents ,Microbial Sensitivity Tests ,Quinolones ,HeLa Cell ,Virus Replication ,01 natural sciences ,Article ,03 medical and health sciences ,Drug Discovery ,Humans ,Ribonuclease H, Human Immunodeficiency Viru ,Magnesium ,AIDS ,HIV ,rNase H inhibitors ,Quinolinonyl non-diketo acid derivatives ,RNase H ,ComputingMilieux_MISCELLANEOUS ,Polymerase ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,Microbial Sensitivity Test ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,Chemistry ,Anti-HIV Agent ,Reverse transcriptase ,Reverse Transcriptase Inhibitor ,3. Good health ,0104 chemical sciences ,Amino acid ,Integrase ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Ribonuclease H, Human Immunodeficiency Virus ,Enzyme ,Biochemistry ,Viral replication ,Docking (molecular) ,Mutation ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,HIV-1 ,Mutagenesis, Site-Directed ,biology.protein ,Reverse Transcriptase Inhibitors ,Molecular Medicine ,Human ,HeLa Cells ,Protein Binding - Abstract
Novel anti-HIV agents are still needed to overcome resistance issues, in particular inhibitors acting against novel viral targets. The ribonuclease H (RNase H) function of the reverse transcriptase (RT) represents a validated and promising target, and no inhibitor has reached the clinical pipeline yet. Here, we present rationally designed non-diketo acid selective RNase H inhibitors (RHIs) based on the quinolinone scaffold starting from former dual integrase (IN)/RNase H quinolinonyl diketo acids. Several derivatives were synthesized and tested against RNase H and viral replication and found active at micromolar concentrations. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, and Mg2+ titration experiments demonstrated that our compounds coordinate the Mg2+ cofactor and interact with amino acids of the RNase H domain that are highly conserved among naïve and treatment-experienced patients. In general, the new inhibitors influenced also the polymerase activity of RT but were selective against RNase H vs the IN enzyme.
- Published
- 2021
25. Carbonic anhydrase activation profile of indole-based derivatives
- Author
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Federico Da Settimo, Sandro Cosconati, Claudia Martini, Eleonora Da Pozzo, Claudiu T. Supuran, Andrea Angeli, Elisabetta Barresi, Barbara Costa, Lorenzo Germelli, Rahul Ravichandran, Emma Baglini, Silvia Salerno, Sabrina Taliani, Anna Maria Marini, Barresi, E., Ravichandran, R., Germelli, L., Angeli, A., Baglini, E., Salerno, S., Marini, A. M., Costa, B., Da Pozzo, E., Martini, C., Da Settimo, F., Supuran, C., Cosconati, S., and Taliani, S.
- Subjects
Models, Molecular ,Indoles ,Cell Survival ,Enzyme Activator ,Proton Magnetic Resonance Spectroscopy ,Enzyme Activators ,microglia ,Enzyme-Linked Immunosorbent Assay ,RM1-950 ,Substrate Specificity ,Carbonic Anhydrase ,brain associated human ca vii isoform ,Carbonic anhydrase ,mental disorders ,Drug Discovery ,Humans ,Carbon-13 Magnetic Resonance Spectroscopy ,Carbonic Anhydrases ,Pharmacology ,Indole test ,Carbonic anhydrase activator ,biology ,Chemistry ,Brain-Derived Neurotrophic Factor ,nutritional and metabolic diseases ,Carbonic anhydrase activators ,brain associated human CA VII isoform ,indole ,General Medicine ,Isoenzyme ,Enzyme Activation ,Isoenzymes ,carbonic anhydrase activators ,Biochemistry ,Ageing ,Spatial learning ,biology.protein ,Therapeutics. Pharmacology ,Human ,Research Article ,Research Paper - Abstract
Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer’s disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.
- Published
- 2021
26. Tetrahydroquinazole-based secondary sulphonamides as carbonic anhydrase inhibitors: synthesis, biological evaluation against isoforms I, II, IV, and IX, and computational studies
- Author
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Claudiu T. Supuran, Anna Maria Marini, Monica Viviano, Federico Da Settimo, Sandro Cosconati, Elisabetta Barresi, Sabrina Taliani, Silvia Salerno, Sabrina Castellano, Emanuela Berrino, Emma Baglini, Rahul Ravichandran, Baglini, E., Ravichandran, R., Berrino, E., Salerno, S., Barresi, E., Marini, A. M., Viviano, M., Castellano, S., Da Settimo, F., Supuran, C. T., Cosconati, S., and Taliani, S.
- Subjects
Gene isoform ,structure–activity relationship ,Carbonic Anhydrase Inhibitor ,carbonic anhydrases inhibitors ,Proton Magnetic Resonance Spectroscopy ,Drug Evaluation, Preclinical ,RM1-950 ,tumour-related ca ix isoform ,secondary sulphonamide ,Structure-Activity Relationship ,Carbonic anhydrase ,Drug Discovery ,Potency ,Carbon-13 Magnetic Resonance Spectroscopy ,Carbonic Anhydrase Inhibitors ,Biological evaluation ,Pharmacology ,Sulfonamides ,Bicyclic molecule ,biology ,tetrahydroquinazole derivative ,Chemistry ,Carbonic anhydrases inhibitor ,Quinazoline ,Computational Biology ,General Medicine ,Isoenzyme ,Isoenzymes ,Molecular Docking Simulation ,secondary sulphonamides ,Biochemistry ,Carbonic anhydrases inhibitors ,structure–activity relationships ,tetrahydroquinazole derivatives ,tumour-related CA IX isoform ,Quinazolines ,biology.protein ,Therapeutics. Pharmacology ,Selectivity ,Research Article ,Research Paper - Abstract
A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure–activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.
- Published
- 2021
27. Development of novel dipeptide nitriles as inhibitors of rhodesain of Trypanosoma brucei rhodesiense
- Author
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Carla Di Chio, Santo Previti, Giorgio Amendola, Rahul Ravichandran, Annika Wagner, Sandro Cosconati, Ute A. Hellmich, Tanja Schirmeister, Maria Zappalà, Roberta Ettari, Di Chio, C., Previti, S., Amendola, G., Ravichandran, R., Wagner, A., Cosconati, S., Hellmich, U. A., Schirmeister, T., Zappala, M., and Ettari, R.
- Subjects
Trypanosoma brucei rhodesiense ,Pharmacology ,Dipeptide nitrile ,Organic Chemistry ,Dipeptides ,General Medicine ,Cysteine Proteinase Inhibitors ,Antitrypanosomal agent ,Trypanocidal Agents ,Cysteine Endopeptidases ,Structure-Activity Relationship ,Docking studie ,Nitriles ,Drug Discovery ,Rhodesain inhibitors ,Cysteine protease - Abstract
In this paper, we developed a new series of dipeptide nitriles that were demonstrated to be reversible rhodesain inhibitors at nanomolar level, with EC50 values against cultured T. b. brucei in the micromolar range. We also proved that our dipeptide nitriles directly bind to the active site of rhodesain acting as competitive inhibitors. Within the most interesting compounds, the dipeptide nitrile 2b showed the highest binding affinity towards rhodesain (Ki = 16 nM) coupled with a good antiparasitic activity (EC50 = 14.1 μM). Moreover, for the dipeptide nitrile 3e, which showed a Ki = 122 nM towards the trypanosomal protease, we obtained the highest antiparasitic activity (EC50 = 8.8 μM). Thus, given the obtained results both compounds could certainly represent new lead compounds for the discovery of new drugs to treat Human African Trypanosomiasis.
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- 2022
28. A novel smaller β‐defensin‐derived peptide is active against multidrug‐resistant bacterial strains
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Elena Scaglione, Francesco Salvatore, Chiara Pagliuca, Aurora Daniele, Antonello Pessi, Fortunata Carbone, Sandro Cosconati, Roberta Colicchio, Stefano Tomassi, Salvatore Di Maro, Irene Colavita, Maria Vincenza Carriero, Paola Salvatore, Giuseppe Matarese, Ersilia Nigro, Colicchio, R., Nigro, E., Colavita, I., Pagliuca, C., Di Maro, S., Tomassi, S., Scaglione, E., Carbone, F., Carriero, M. V., Matarese, G., Daniele, A., Cosconati, S., Pessi, A., Salvatore, F., Salvatore, P., Colicchio, Roberta, Nigro, Ersilia, Colavita, Irene, Pagliuca, Chiara, Di Maro, Salvatore, Tomassi, Stefano, Scaglione, Elena, Carbone, Fortunata, Carriero, Maria Vincenza, Matarese, Giuseppe, Daniele, Aurora, Cosconati, Sandro, Pessi, Antonello, Salvatore, Francesco, and Salvatore, Paola
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beta-Defensins ,medicine.drug_class ,Antibiotics ,Antimicrobial peptides ,multidrug-resistant bacteria ,Peptide ,Microbial Sensitivity Tests ,Biochemistry ,Microbiology ,chemistry.chemical_compound ,Antibiotic resistance ,Drug Resistance, Multiple, Bacterial ,Anti-Bacterial Agent ,Genetics ,Peptide synthesis ,medicine ,Humans ,γ-core ,Molecular Biology ,Defensin ,chemistry.chemical_classification ,antimicrobial activity ,Bacteria ,Microbial Sensitivity Test ,Antimicrobial Peptide ,Biofilm ,peptide synthesi ,Anti-Bacterial Agents ,Multiple drug resistance ,chemistry ,Biofilms ,human β-defensin 3 ,Antimicrobial Peptides ,Human ,Biotechnology - Abstract
Antibiotic resistance is becoming a severe obstacle in the fight against acute and chronic infectious diseases that accompany most degenerative illnesses from neoplasia to osteo-arthritis and obesity. Currently, the race is on to identify pharmaceutical molecules or combinations of molecules able to prevent or reduce the insurgence and/or progression of infectivity. Attempts to substitute antibiotics with antimicrobial peptides have, thus far, met with little success against multidrug-resistant (MDR) bacterial strains. During the last decade, we designed and studied the activity and features of human β-defensin analogs, which are salt-resistant, and hence active also under high salt concentrations as, for instance, in cystic fibrosis. Herein, we describe the design, synthesis, and major features of a new 21 aa long molecule, peptide γ2. The latter derives from the γ-core of the β-defensin natural molecules, a small fragment of these molecules still bearing high antibacterial activity. We found that peptide γ2, which contains only one disulphide bond, recapitulates most of the biological properties of natural human β-defensins and can also counteract both Gram-positive and Gram-negative MDR bacterial strains and biofilm formation. Moreover, it has great stability in human serum thereby enhancing its antibacterial presence and activity without cytotoxicity in human cells. In conclusion, peptide γ2 is a promising new weapon also in the battle against intractable infectious diseases.
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- 2021
29. PyRMD: A New Fully Automated AI-Powered Ligand-Based Virtual Screening Tool
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Sandro Cosconati, Giorgio Amendola, Amendola, G., and Cosconati, S.
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Virtual screening ,Boosting (machine learning) ,Computer science ,business.industry ,General Chemical Engineering ,General Chemistry ,Library and Information Sciences ,Machine learning ,computer.software_genre ,chEMBL ,Ligands ,Computer Science Applications ,Identification (information) ,Workflow ,Software ,Artificial Intelligence ,Drug Discovery ,Benchmark (computing) ,Artificial intelligence ,business ,computer ,Algorithms ,Coding (social sciences) - Abstract
Artificial intelligence (AI) algorithms are dramatically redefining the current drug discovery landscape by boosting the efficiency of its various steps. Still, their implementation often requires a certain level of expertise in AI paradigms and coding. This often prevents the use of these powerful methodologies by non-expert users involved in the design of new biologically active compounds. Here, the random matrix discriminant (RMD) algorithm, a high-performance AI method specifically tailored for the identification of new ligands, was implemented in a new fully automated tool, PyRMD. This ligand-based virtual screening tool can be trained using target bioactivity data directly downloaded from the ChEMBL repository without manual intervention. The software automatically splits the available training compounds into active and inactive sets and learns the distinctive chemical features responsible for the compounds' activity/inactivity. PyRMD was designed to easily screen millions of compounds in hours through an automated workflow and intuitive input files, allowing fine tuning of each parameter of the calculation. Additionally, PyRMD features a wealth of benchmark metrics, to accurately probe the model performance, which were used here to gauge its predictive potential and limitations. PyRMD is freely available on GitHub (https://github.com/cosconatilab/PyRMD) as an open-source tool.
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- 2021
30. Novel 2-substituted-benzimidazole-6-sulfonamides as carbonic anhydrase inhibitors: synthesis, biological evaluation against isoforms I, II, IX and XII and molecular docking studies
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Ettore Novellino, Alessio Nocentini, Sandro Cosconati, Sabrina Castellano, Alessandra Feoli, Federico Da Settimo, Elisabetta Barresi, Giorgio Amendola, Sabrina Taliani, Claudiu T. Supuran, Alessandra Cipriano, Silvia Bua, Ciro Milite, Milite, C., Amendola, G., Nocentini, A., Bua, S., Cipriano, A., Barresi, E., Feoli, A., Novellino, E., Da Settimo, F., Supuran, C. T., Castellano, S., Cosconati, S., and Taliani, S.
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Gene isoform ,Benzimidazole ,Carbonic anhydrase inhibitors, benzimidazole-sulfonamides, reduced flexibility approach, isoform-selective inhibitors, molecular docking ,Carbonic Anhydrase I ,Nerve Tissue Proteins ,benzimidazole-sulfonamide ,Carbonic Anhydrase II ,Structure-Activity Relationship ,chemistry.chemical_compound ,isoform-selective inhibitors ,Carbonic anhydrase ,Drug Discovery ,Humans ,isoform-selective inhibitor ,Amines ,benzimidazole-sulfonamides ,Carbonic anhydrase inhibitors ,molecular docking ,reduced flexibility approach ,Benzimidazoles ,Carbonic Anhydrase Inhibitors ,Carbonic Anhydrases ,Isoenzymes ,Molecular Docking Simulation ,Molecular Structure ,Schiff Bases ,Sulfonamides ,Carbonic anhydrase inhibitor ,Biological evaluation ,Pharmacology ,chemistry.chemical_classification ,biology ,Chemistry ,lcsh:RM1-950 ,General Medicine ,Transmembrane protein ,Enzyme inhibition ,lcsh:Therapeutics. Pharmacology ,Enzyme ,Biochemistry ,biology.protein ,Selectivity ,Research Paper - Abstract
Inhibition of Carbonic Anhydrases (CAs) has been clinically exploited for many decades for a variety of therapeutic applications. Within a research project aimed at developing novel classes of CA inhibitors (CAIs) with a proper selectivity for certain isoforms, a series of derivatives featuring the 2-substituted-benzimidazole-6-sulfonamide scaffold, conceived as frozen analogs of Schiff bases and secondary amines previously reported in the literature as CAIs, were investigated. Enzyme inhibition assays on physiologically relevant human CA I, II, IX and XII isoforms revealed a number of potent CAIs, showing promising selectivity profiles towards the transmembrane tumor-associated CA IX and XII enzymes. Computational studies were attained to clarify the structural determinants behind the activities and selectivity profiles of the novel inhibitors., Graphical Abstract
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- 2019
31. Lead Discovery of SARS-CoV-2 Main Protease Inhibitors through Covalent Docking-Based Virtual Screening
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Tanja Schirmeister, Robert A. Zimmermann, Carla Di Chio, Collin Zimmer, Giorgio Amendola, Santo Previti, Anna Messere, Roberta Ettari, Stefan Hammerschmidt, Sandro Cosconati, Salvatore Di Maro, Maria Zappalà, Amendola, G., Ettari, R., Previti, S., Di Chio, C., Messere, A., Di Maro, S., Hammerschmidt, S. J., Zimmer, C., Zimmermann, R. A., Schirmeister, T., Zappala, M., and Cosconati, S.
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Coronavirus disease 2019 (COVID-19) ,General Chemical Engineering ,medicine.medical_treatment ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,In silico ,Computational biology ,Library and Information Sciences ,01 natural sciences ,Molecular Docking Simulation ,Antiviral Agents ,Article ,Docking (dog) ,0103 physical sciences ,medicine ,Humans ,Protease Inhibitors ,Pandemics ,Virtual screening ,Protease ,010304 chemical physics ,business.industry ,SARS-CoV-2 ,COVID-19 ,General Chemistry ,0104 chemical sciences ,Computer Science Applications ,010404 medicinal & biomolecular chemistry ,Target protein ,business - Abstract
During almost all 2020, coronavirus disease 2019 (COVID-19) pandemic has constituted the major risk for the worldwide health and economy, propelling unprecedented efforts to discover drugs for its prevention and cure. At the end of the year, these efforts have culminated with the approval of vaccines by the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA) giving new hope for the future. On the other hand, clinical data underscore the urgent need for effective drugs to treat COVID-19 patients. In this work, we embarked on a virtual screening campaign against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mpro chymotrypsin-like cysteine protease employing our in-house database of peptide and non-peptide ligands characterized by different types of warheads acting as Michael acceptors. To this end, we employed the AutoDock4 docking software customized to predict the formation of a covalent adduct with the target protein. In vitro verification of the inhibition properties of the most promising candidates allowed us to identify two new lead inhibitors that will deserve further optimization. From the computational point of view, this work demonstrates the predictive power of AutoDock4 and suggests its application for the in silico screening of large chemical libraries of potential covalent binders against the SARS-CoV-2 Mpro enzyme.
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- 2021
32. Structure-Activity Relationship Studies on Oxazolo[3,4- a]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent in Vivo Activity
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Girolamo Calò, Federica Ferrari, Chiara Ruzza, Giorgio Amendola, Sandro Cosconati, Rainer K Reinscheid, Erika Marzola, Chiara Sturaro, Tatiana Bernardi, Salvatore Pacifico, Claudio Trapella, Valentina Albanese, Anna Fantinati, Delia Preti, Martina Fabbri, Remo Guerrini, Albanese, V., Ruzza, C., Marzola, E., Bernardi, T., Fabbri, M., Fantinati, A., Trapella, C., Reinscheid, R. K., Ferrari, F., Sturaro, C., Calo, G., Amendola, G., Cosconati, S., Pacifico, S., Guerrini, R., and Preti, D.
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Receptors, Neuropeptide ,Oxazoles ,Receptors, G-Protein-Coupled ,Structure-Activity Relationship ,Pharmacology ,01 natural sciences ,Article ,NO ,03 medical and health sciences ,G-Protein-Coupled ,In vivo ,Drug Discovery ,Neuropeptide S ,Receptors ,Structure–activity relationship ,Animals ,Humans ,Receptor ,Neuropeptide S receptor ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Molecular Structure ,Chemistry ,Antagonist ,Ligand (biochemistry) ,In vitro ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Neuropeptide ,HEK293 Cells ,Pyrazines ,Molecular Medicine ,Locomotion ,Protein Binding - Abstract
Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists in vitro have been discovered which, however, require further optimization of their in vivo pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4-a]pyrazine class. The guanidine derivative 16 exhibited nanomolar activity in vitro and 5-fold improved potency in vivo compared to SHA-68, a reference pharmacological tool in this field. Compound 16 can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure-activity relationships and provide an updated model of ligand/NPSR interactions.
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- 2021
33. Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense
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Giorgio Amendola, Carla Di Chio, Santo Previti, Roberta Ettari, Sandro Cosconati, Maria Zappalà, Tanja Schirmeister, Di Chio, C., Previti, S., Amendola, G., Cosconati, S., Schirmeister, T., Zappala, M., and Ettari, R.
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Trypanosoma brucei rhodesiense ,human African trypanosomiasi ,Stereochemistry ,Peptidomimetic ,medicine.medical_treatment ,Substituent ,Antiprotozoal Agents ,Trypanosoma brucei ,Cysteine Proteinase Inhibitors ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Benzodiazepines ,Structure-Activity Relationship ,Drug Development ,Parasitic Sensitivity Tests ,Drug Discovery ,medicine ,Moiety ,General Pharmacology, Toxicology and Pharmaceutics ,Peptide sequence ,Pharmacology ,rhodesain ,Protease ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,benzodiazepine scaffold ,biology.organism_classification ,peptidomimetic ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Cysteine Endopeptidases ,chemistry ,Molecular Medicine ,Peptidomimetics ,Michael acceptor ,Lead compound - Abstract
Starting from the reversible rhodesain inhibitors 1 a-c, which have Ki values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i. e., 2 g) with a k2nd value of 90 000 M-1 min-1 that showed antitrypanosomal activity in the low-micromolar range (EC50 =1.25 μM), this may be considered a promising lead compound in the drug-discovery process for treating human African trypanosomiasis (HAT).
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- 2020
34. Disulfide bond replacement with 1,4‐ and 1,5‐disubstituted [1,2,3]‐triazole on C‐X‐C chemokine receptor type 4 (CXCR4) peptide ligands: small changes that make big differences
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Stefania Scala, Ettore Novellino, Diego Brancaccio, Alfonso Carotenuto, Vincenzo Maria D'Amore, Sandro Cosconati, Salvatore Di Maro, Stefano Tomassi, Luciana Marinelli, Francesco Merlino, Federica Santoro, Anna Messere, Francesco Saverio Di Leva, Anna Maria Trotta, Caterina Ieranò, Giuseppina Rea, Tomassi, Stefano, Trotta, Anna Maria, Ieranò, Caterina, Merlino, Francesco, Messere, Anna, Rea, Giuseppina, Santoro, Federica, Brancaccio, Diego, Carotenuto, Alfonso, D'Amore, Vincenzo Maria, Di Leva, Francesco Saverio, Novellino, Ettore, Cosconati, Sandro, Scala, Stefania, Marinelli, Luciana, Di Maro, Salvatore, Tomassi, S., Trotta, A. M., Ierano, C., Merlino, F., Messere, A., Rea, G., Santoro, F., Brancaccio, D., Carotenuto, A., D'Amore, V. M., Di Leva, F. S., Novellino, E., Cosconati, S., Marinelli, L., Scala, S., and Di Maro, S.
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Agonist ,Receptors, CXCR4 ,1,4-triazole ,1,2,3-Triazole ,Stereochemistry ,Peptidomimetic ,medicine.drug_class ,Peptide ,010402 general chemistry ,Ligands ,01 natural sciences ,Catalysis ,Chemokine receptor ,chemistry.chemical_compound ,Cell surface receptor ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Disulfides ,Receptor ,chemistry.chemical_classification ,Disulfide bond ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,1,5-triazole ,General Chemistry ,Triazoles ,Cyclic peptide ,Chemokine CXCL12 ,0104 chemical sciences ,Peptidomimetics ,CXCR4 receptor ,Peptides - Abstract
Here we investigatethe structural and biological effects ensuing form the disulfide bond replacement of a potent and selective C-X-C chemokine receptor type 4 (CXCR4) peptide antagonist, with 1,4- and 1,5- disubstituted 1,2,3-triazole moieties. Both strategies produced candidates that showed high affinity and selectivity against CXCR4. Notably, when assessed for their ability to modulate the CXCL12-mediated cell migration, the 1,4-triazole variant conserved the antagonistic effect in the low-mid nanomolar range, while the 1,5-triazole one displayed the ability to activate the migration, becoming the first in class low-molecular-weight CXCR4 peptide agonist. By combining NMR and computational studies, we provided a valuable model that highlighted differences in the interactions of the two peptidomimetics with the receptor that could account for their different functional profile. Finally, we envisage that our findings could be translated to different GPCR-interacting peptides for the pursuit of novel chemical probes that could assist in dissecting the complex puzzle of this fundamental class of transmembrane receptors.
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- 2020
35. New insights in the structure-activity relationships of 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors
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Francesca Simorini, Lisa Dalla Via, Stefano Tomassi, Giorgio Amendola, Sabrina Taliani, Concettina La Motta, Anna Maria Marini, Elisabetta Barresi, Federico Da Settimo, Silvia Salerno, Ettore Novellino, Sandro Cosconati, Aída Nelly García-Argáez, Salerno, Silvia, García-Argáez, Aída Nelly, Barresi, Elisabetta, Taliani, Sabrina, Simorini, Francesca, La Motta, Concettina, Amendola, Giorgio, Tomassi, Stefano, Cosconati, Sandro, Novellino, Ettore, Da Settimo, Federico, Marini, Anna Maria, Via, Lisa Dalla, Salerno, S, García-Argáez, An, Barresi, E, Taliani, S, Simorini, F, La Motta, C, Amendola, G, Tomassi, S, Cosconati, S, Novellino, E, Da Settimo, F, Marini, Am, and Via, Ld.
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Models, Molecular ,0301 basic medicine ,Pyrimidine ,medicine.drug_class ,Angiogenesis ,Antineoplastic Agents ,Antiproliferative activity ,Monoclonal antibody ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Drug Discovery ,Human Umbilical Vein Endothelial Cells ,medicine ,Humans ,Protein Kinase Inhibitors ,Cell Proliferation ,Pyrans ,Pharmacology ,Kinase inhibitor ,Aniline Compounds ,Dose-Response Relationship, Drug ,Molecular Structure ,Kinase ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Kinase insert domain receptor ,General Medicine ,Vascular Endothelial Growth Factor Receptor-2 ,Small molecule ,Benzothiopyranopyrimidine ,Pyrimidines ,030104 developmental biology ,chemistry ,Biochemistry ,Kinase inhibitors ,Cell culture ,KDR kinase ,030220 oncology & carcinogenesis ,Drug Screening Assays, Antitumor ,Benzothiopyranopyrimidines ,Signal transduction - Abstract
Inhibition of angiogenesis via blocking vascular endothelial growth factor receptor (VEGFR) signaling pathway emerged as an established approach in anticancer therapy. So far, many monoclonal antibodies and ATP-competitive small molecule inhibitors have been clinically validated and approved. In this study, structure-activity relationships (SAR) within the 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidine class of kinase inhibitors were further refined by the synthesis and biological evaluation of new compounds 1–21 featuring different substitution patterns on the pendant phenyl moiety, combined with H, OCH3, or Cl at 8-position. Most compounds showed a promising human kinase insert domain receptor (KDR) inhibition profile, with IC50 values in the submicromolar/low micromolar range, and promising antiproliferative activity on human umbilical vein endothelial cells (HUVECs) as well as on a panel of three human tumor cell lines. The angio-kinase selectivity profile was assessed for the most promising compound 16 against a set of six human kinases. Finally, computational studies allowed clarifying at molecular level the interaction pattern established by the compounds with KDR, highlighting key stable cation-π interactions, and thus providing the basis for further designing novel inhibitors.
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- 2018
36. Structure-activity relationship of the exopolysaccharide from a psychrophilic bacterium: A strategy for cryoprotection
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Rosa Lanzetta, Ettore Novellino, Matthew I. Gibson, Ermenegilda Parrilli, Filomena Sannino, Angela Casillo, Daniel E. Mitchell, Gennaro Marino, Michelangelo Parrilli, Maria Luisa Tutino, Antonio Randazzo, Sandro Cosconati, Maria Michela Corsaro, Casillo, Angela, Parrilli, Ermenegilda, Sannino, Filomena, Mitchell, Daniel E., Gibson, Matthew I., Marino, Gennaro, Lanzetta, Rosa, Parrilli, Michelangelo, Cosconati, Sandro, Novellino, Ettore, Randazzo, Antonio, Tutino, Maria L., Corsaro, M. Michela, Mitchell, D. E., Gibson, M, Marino, G, Cosconati, S, Tutino, MARIA LUISA, and Corsaro, MARIA MICHELA
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0301 basic medicine ,Magnetic Resonance Spectroscopy ,Recrystallization (geology) ,Polymers and Plastics ,Exopolymer ,030106 microbiology ,Article ,Structure-Activity Relationship ,03 medical and health sciences ,Cryoprotective Agents ,NMR spectroscopy ,Cold-adaptation ,Materials Chemistry ,Structure–activity relationship ,Psychrophile ,Protein secondary structure ,Alanine ,biology ,Chemistry ,QH ,Alteromonadaceae ,Colwellia psychrerythraea 34H ,Ice ,Polysaccharides, Bacterial ,Organic Chemistry ,Nuclear magnetic resonance spectroscopy ,Alanine decoration ,biology.organism_classification ,3. Good health ,Cold Temperature ,030104 developmental biology ,Biochemistry ,Alanine decoration, Cold adaptation, Colwellia psychrerythraea 34H, Exopolymer, NMR spectroscopy, Polymers and Plastics, Organic Chemistry ,Bacteria - Abstract
Microrganisms from sea ice, glacial and subglacial environments are currently under investigation due to their relevant ecological functions in these habitats, and to their potential biotechnological applications. The cold-adapted Colwellia psychrerythraea 34H produces extracellular polysaccharides with cryoprotection activity. We here describe the purification and detailed molecular primary and secondary structure of the exopolysaccharide (EPS) secreted by C. psychrerythraea 34H cells grown at 4 °C. The structure was determined by chemical analysis and NMR. The trisaccharide repeating unit of the EPS is constituted by a N-acetyl quinovosamine unit and two residues of galacturonic acid both decorated with alanine. In addition, the EPS was tested in vitro showing a significant inhibitory effect on ice recrystallization. In-depth NMR and computational analysis suggest a pseudohelicoidal structure which seems to prevent the local tetrahedral order of the water molecules in the first hydration shell, and could be responsible of the inhibition of ice recrystallization.\ud As cell cryopreservation is an essential tool in modern biotechnology and medicine, the observations reported in this paper could pave the way for a biotechnological application of Colwellia EPS.
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- 2017
37. Discovery of dihydroxyindole-2-carboxylic acid derivatives as dual allosteric HIV-1 Integrase and Reverse Transcriptase associated Ribonuclease H inhibitors
- Author
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Mamuka Kvaratskhelia, Pratibha C. Koneru, Ettore Novellino, Nicolino Pala, Vincenzo Maria D'Amore, Francesca Esposito, Adele Sanna, Sandro Cosconati, Nicole Grandi, Enzo Tramontano, Francesco Saverio Di Leva, Lieve Naesens, Angela Corona, Roberto Di Santo, Mario Sechi, Esposito, Francesca, Sechi, Mario, Pala, Nicolino, Sanna, Adele, Koneru, Pratibha Chowdary, Kvaratskhelia, Mamuka, Naesens, Lieve, Corona, Angela, Grandi, Nicole, di Santo, Roberto, D'Amore, Vincenzo Maria, Di Leva, Francesco Saverio, Novellino, Ettore, Cosconati, Sandro, Tramontano, Enzo, Esposito, F., Sechi, M., Pala, N., Sanna, A., Koneru, P. C., Kvaratskhelia, M., Naesens, L., Corona, A., Grandi, N., di Santo, R., D'Amore, V. M., Di Leva, F. S., Novellino, E., Cosconati, S., and Tramontano, E.
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0301 basic medicine ,dihydroxyindole-2-carboxylic acids ,hiv dual inhibitors ,in ,in-ledgf binding inhibitors ,rnase h ,sucrose binding site ,carboxylic acids ,cell line ,drug discovery ,hiv infections ,hiv integrase ,hiv integrase inhibitors ,hiv reverse transcriptase ,hiv-1 ,humans ,molecular docking simulation ,molecular structure ,ribonuclease h, human immunodeficiency virus ,structure-activity relationship ,Carboxylic acid ,HIV dual inhibitor ,030106 microbiology ,Allosteric regulation ,IN-LEDGF binding inhibitor ,Carboxylic Acids ,HIV Infections ,HIV Integrase ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Virology ,Drug Discovery ,Humans ,HIV Integrase Inhibitors ,ribonuclease h ,RNase H ,Pharmacology ,chemistry.chemical_classification ,human immunodeficiency virus ,biology ,Molecular Structure ,DHICA ,Reverse transcriptase ,HIV Reverse Transcriptase ,Integrase ,Molecular Docking Simulation ,030104 developmental biology ,Ribonuclease H, Human Immunodeficiency Virus ,Biochemistry ,chemistry ,Viral replication ,Docking (molecular) ,Dihydroxyindole-2-carboxylic acid ,biology.protein ,HIV-1 - Abstract
The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection of drug-resistant strains. A new opportunity for drug intervention is offered by antivirals that act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) and Reverse Transcriptase associated Ribonuclease H (RNase H) activities. Among the tested compounds, the dihydroxyindole-carboxamide 5 was able to inhibit in the low micromolar range (1-18 μM) multiple functions of IN, including functional IN-IN interactions, IN-LEDGF/p75 binding and IN catalytic activity. Docking and site-directed mutagenesis studies have suggested that compound 5 binds to a previously described HIV-1 IN allosteric pocket. These observations indicate that 5 is structurally and mechanistically distinct from the published allosteric HIV-1 IN inhibitors. Moreover, compound 5 also inhibited HIV-1 RNase H function, classifying this molecule as a dual HIV-1 IN and RNase H inhibitor able to impair the HIV-1 virus replication in cell culture. Overall, we identified a new scaffold as a suitable platform for the development of novel dual HIV-1 inhibitors. The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection of drug-resistant strains. A new opportunity for drug intervention is offered by antivirals that act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) and Reverse Transcriptase associated Ribonuclease H (RNase H) activities. Among the tested compounds, the dihydroxyindole-carboxamide 5 was able to inhibit in the low micromolar range (1–18 μM) multiple functions of IN, including functional IN-IN interactions, IN-LEDGF/p75 binding and IN catalytic activity. Docking and site-directed mutagenesis studies have suggested that compound 5 binds to a previously described HIV-1 IN allosteric pocket. These observations indicate that 5 is structurally and mechanistically distinct from the published allosteric HIV-1 IN inhibitors. Moreover, compound 5 also inhibited HIV-1 RNase H function, classifying this molecule as a dual HIV-1 IN and RNase H inhibitor able to impair the HIV-1 virus replication in cell culture. Overall, we identified a new scaffold as a suitable platform for the development of novel dual HIV-1 inhibitors.
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- 2019
38. Discovery of Pyrido[3′,2′:5,6]thiopyrano[4,3-d]pyrimidine-Based Antiproliferative Multikinase Inhibitors
- Author
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Giorgio Amendola, Sabrina Taliani, Sandro Cosconati, Ettore Novellino, Aída Nelly García-Argáez, Elisabetta Barresi, Federico Da Settimo, Stefano Tomassi, Francesca Simorini, Silvia Salerno, Anna Maria Marini, Lisa Dalla Via, Silviasalerno, Elisabettabarresi, AídaNellyGarcía-Argaéz, Sabrinataliani, Francescasimorini, Giorgio, Amendola, Tomassi, S, Sandro, Cosconati, Novellino, Ettore, Federico Da Settimo, Anna Maria Marini, Lisa Dalla Via, Salerno, S., Barresi, E., Garcia-Argaez, A. N., Taliani, S., Simorini, F., Amendola, G., Tomassi, S., Cosconati, S., Novellino, E., Da Settimo, F., Marini, A. M., and Dalla Via, L.
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antiproliferative activity ,Pyridothiopyranopyrimidines ,Pyrimidine ,Angiogenesis ,Kinase ,Organic Chemistry ,Pyridothiopyranopyrimidine ,Biochemistry ,Multikinase inhibitor ,Human tumor ,chemistry.chemical_compound ,chemistry ,Cell culture ,KDR kinase ,Drug Discovery ,Cancer cell ,multitargeted kinase inhibitors ,Cancer research ,Tumor growth ,multitargeted kinase inhibitor - Abstract
[Image: see text] Protein kinases dysregulation is extremely common in cancer cells, and the development of new agents able to simultaneously target multiple kinase pathways involved in angiogenesis and tumor growth may offer several advantages in the treatment of cancer. Herein we report the discovery of new pyridothiopyranopyrimidine derivatives (2–4) showing high potencies in VEGFR-2 KDR inhibition as well as antiproliferative effect on a panel of human tumor cell lines. Investigation on the selectivity profile of the representative 2-anilino-substituted compounds 3b, 3i, and 3j revealed a multiplicity of kinase targets that should account for the potent antiproliferative effect produced by these pyridothiopyranopyrimidine derivatives.
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- 2019
39. Discovery of a novel chemotype of histone lysine methyltransferase EHMT1/2 (GLP/G9a) inhibitors: rational design, synthesis, biological evaluation and co-crystal structure
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Xiaodong Cheng, Alessandra Cipriano, Ettore Novellino, John R. Horton, Giorgio Amendola, Giacomo Pepe, Donatella Rescigno, Gianluca Sbardella, Sabrina Castellano, Alessandra Feoli, Sandro Cosconati, Monica Viviano, Vincenzo Pisapia, Ciro Milite, Milite, C., Feoli, A., Horton, J. R., Rescigno, D., Cipriano, A., Pisapia, V., Viviano, M., Pepe, G., Amendola, G., Novellino, E., Cosconati, S., Cheng, X., Castellano, S., and Sbardella, G.
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Cell Membrane Permeability ,Methyltransferase ,GLP ,Drug Evaluation, Preclinical ,SELECTIVE INHIBITORS ,G9A INHIBITOR ,Crystallography, X-Ray ,01 natural sciences ,DNA methyltransferase ,Article ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,EHMT1 ,Cell Line, Tumor ,Drug Discovery ,Quinazoline ,Humans ,ASSAY ,Enzyme Inhibitors ,DNA METHYLATION ,030304 developmental biology ,0303 health sciences ,Molecular Structure ,Rational design ,CHEMICAL PROBE ,Histone-Lysine N-Methyltransferase ,G9A-LIKE PROTEIN ,Small molecule ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Diazepine ,Biochemistry ,chemistry ,HISTONE/PROTEIN METHYLTRANSFERASE ,Blood-Brain Barrier ,Drug Design ,Molecular Medicine ,SMALL-MOLECULE INHIBITORS ,H3K9 METHYLATION - Abstract
Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of nonquinazoline inhibitors of H3K9-specific methyltransferases G9a and G9a-like protein (GLP) have been reported. Herein, we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the underinvestigated 2-alkyl-5-amino- and 2-aryl-5-amino-substituted 3 H-benzo[ e][1,4]diazepine scaffold. Our research efforts resulted in the identification 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNA methyltransferase 1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both parallel artificial membrane permeability assay (PAMPA) and blood-brain barrier-specific PAMPA, and therefore might potentially be a better candidate for animal studies. Finally, the co-crystal structure of GLP in complex with 12a provides the basis for the further development of benzodiazepine-based G9a/GLP inhibitors. Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of nonquinazoline inhibitors of H3K9-specific methyltransferases G9a and G9a-like protein (GLP) have been reported. Herein, we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the underinvestigated 2-alkyl-5-amino- and 2-aryl-5-amino-substituted 3H-benzo[e][1,4]diazepine scaffold. Our research efforts resulted in the identification 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNA methyltransferase 1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both parallel artificial membrane permeability assay (PAMPA) and blood-brain barrier-specific PAMPA, and therefore might potentially be a better candidate for animal studies. Finally, the co-crystal structure of GLP in complex with 12a provides the basis for the further development of benzodiazepine-based G9a/GLP inhibitors.
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- 2019
40. Identification of novel indole derivatives acting as inhibitors of the Keap1-Nrf2 interaction
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Giampietro Viola, Giorgio Amendola, Roberta Bortolozzi, Sandro Cosconati, Giovanni Greco, Sonia Laneri, Barbara Cosimelli, Antonia Sacchi, Ettore Novellino, Cosimelli, Barbara, Greco, Giovanni, Laneri, Sonia, Novellino, Ettore, Sacchi, Antonia, Amendola, Giorgio, Cosconati, Sandro, Bortolozzi, Roberta, Viola, Giampietro, Cosimelli, B., Greco, G., Laneri, S., Novellino, E., Sacchi, A., Amendola, G., Cosconati, S., Bortolozzi, R., and Viola, G.
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Models, Molecular ,Indoles ,NF-E2-Related Factor 2 ,Short Communication ,Keap1–Nrf2-ARE system ,Transketolase ,Quinone oxidoreductase ,01 natural sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,antioxidant response element ,Drug Discovery ,Humans ,oxidative stress ,Transcription factor ,Pharmacology ,chemistry.chemical_classification ,Indole test ,Reporter gene ,oxidative stre ,Kelch-Like ECH-Associated Protein 1 ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,lcsh:RM1-950 ,General Medicine ,Keap1–Nrf2 interaction ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Enzyme ,lcsh:Therapeutics. Pharmacology ,chemistry ,Biochemistry ,Docking (molecular) ,Zwitterion ,Indole derivatives ,Indole derivative ,HeLa Cells ,Protein Binding - Abstract
Nine indole derivatives (9a-i) were tested as potential inhibitors of the Keap1–Nrf2 interaction. This class of compounds increases the intracellular levels of the transcription factor Nrf2 and the consequent expression of enzymes encoded by genes containing the antioxidant response element (ARE). In the ARE-luciferase reporter assay only 9e-g revealed to be remarkably more active than t-butylhydroxyquinone (t-BHQ), with 9g standing out as the best performing compound. While 9e and 9f are weak acids, 9g is an ampholyte prevailing as a zwitterion in neutral aqueous solutions. The ability of 9e-g to significantly increase levels of Nrf2, NADPH:quinone oxidoreductase 1, and transketolase (TKT) gave further support to the hypothesis that these compounds act as inhibitors of the Keap1–Nrf2 interaction. Docking simulations allowed us to elucidate the nature of the putative interactions between 9g and Keap1., GRAPHICAL ABSTRACT
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- 2019
41. Antitumor efficacy of Kisspeptin in human malignant mesothelioma cells
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Roberto Bianco, Floriana Morgillo, Sandro Cosconati, Stefano Tomassi, Fortunato Ciardiello, Carminia Maria Della Corte, Concetta Di Mauro, Rosaria Meccariello, Teresa Troiani, Salvatore Di Maro, Riccardo Pierantoni, Vincenza Ciaramella, Rosanna Chianese, Erika Martinelli, Ciaramella, V, Della Corte, Cm, Di Mauro, C, Tomassi, S, Di Maro, S, Troiani, T, Martinelli, E, Bianco, R, Cosconati, S, Pierantoni, R, Meccariello, R, Chianese, R, Ciardiello, F, Morgillo, F., and DELLA CORTE, Carminia Maria
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0301 basic medicine ,Metastatic phenotype ,Tumor cells ,Metastasi ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Kisspeptin ,medicine ,metastasis ,Mesothelioma ,business.industry ,Metastasis formation ,EMT ,KiSS1 ,medicine.disease ,030104 developmental biology ,Oncology ,mesothelioma ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biomarker ,business ,After treatment ,Research Paper - Abstract
// Vincenza Ciaramella 1 , Carminia Maria Della Corte 1 , Concetta Di Mauro 2 , Stefano Tomassi 3 , Salvatore Di Maro 3 , Teresa Troiani 1 , Erika Martinelli 1 , Roberto Bianco 2 , Sandro Cosconati 3 , Riccardo Pierantoni 4 , Rosaria Meccariello 5 , Rosanna Chianese 4 , Fortunato Ciardiello 1 and Floriana Morgillo 1 1 Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Universita degli Studi della Campania Luigi Vanvitelli, Naples, Italy 2 Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli “Federico II”, Naples, Italy 3 DISTABIF, Universita degli Studi della Campania Luigi Vanvitelli, Caserta, Italy 4 Dipartimento di Medicina Sperimentale sez ‘F. Bottazzi’, Universita degli Studi della Campania Luigi Vanvitelli, Naples, Italy 5 Dipartimento di Scienze Motorie e del Benessere, Universita di Napoli Parthenope, Napoli, Italy Correspondence to: Floriana Morgillo, email: florianamorgillo@yahoo.com Keywords: mesothelioma; KiSS1; biomarker; metastasis; EMT Received: February 03, 2018 Accepted: February 27, 2018 Published: April 10, 2018 ABSTRACT Purpose: Kisspeptin signaling, via its receptors GPR54, could be an essential players in the inhibition of mesothelioma progression, invasion and metastasis formation. The loss of KiSS1 by tumor cells has been associated with a metastatic phenotype but the mechanistic insights of this process are still unknown. Experimental design: The blockade of the metastatic process at early stage is a hot topic in cancer research. We studied the role of KiSS1 on proliferation, invasiveness, migration abilities of mesothelioma cell lines focusing on the effect on epithelial-to-mesenchymal transition (EMT). Results: Treatment with the KiSS1 peptide or with a synthesis peptide with longer half-life, the FTM080, significantly inhibited cell proliferation, migration and invasion of mesothelioma cell lines; the same treatment reduced the activity of MMP-2 and MMP-9 determining consequently a marked reduction in the invasiveness of primary tumors and metastases. Thespecificexpression of EMT markers, as E-caderin, Vimentin, Slug and Snail, suggested the inhibition of EMT after treatment with KiSS1 as well as the preservation of epithelial components. Conclusion: Our results support anti-proliferative effect of KiSS1 in cancer cells and suggest that targeting the KiSS1/GPR54 system may represent a novel therapeutic approach for mesothelioma.
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- 2018
42. Cationic nucleopeptides as novel non-covalent carriers for the delivery of peptide nucleic acid (PNA) and RNA oligomers
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Ilaria Baglivo, Sandro Cosconati, Giuseppina Rea, Maria Napolitano, Rosita Russo, Angela Chambery, Luciana Marinelli, Ersilia Nigro, Paolo V. Pedone, Stefano Tomassi, Maria Emilia Mercurio, Anna Messere, Caterina Ieranò, Aurora Daniele, Stefania Scala, Ettore Novellino, Salvatore Di Maro, Tomassi, Stefano, Ieranò, Caterina, Mercurio, Maria Emilia, Nigro, Ersilia, Daniele, Aurora, Russo, Rosita, Chambery, Angela, Baglivo, Ilaria, Pedone, Paolo Vincenzo, Rea, Giuseppina, Napolitano, Maria, Scala, Stefania, Cosconati, Sandro, Marinelli, Luciana, Novellino, Ettore, Messere, Anna, Di Maro, Salvatore, Tomassi, S, Ieranò, C, Mercurio, Me, Nigro, E, Daniele, A, Russo, R, Chambery, A, Baglivo, I, Pedone, Pv, Rea, G, Napolitano, M, Scala, S, Cosconati, S, Marinelli, L, Novellino, E, Messere, A, and Di Maro, S.
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0301 basic medicine ,Peptide Nucleic Acids ,Cell Membrane Permeability ,Clinical Biochemistry ,Pharmaceutical Science ,Transfection ,Biochemistry ,Nucleobase ,03 medical and health sciences ,chemistry.chemical_compound ,Cations ,Cell Line, Tumor ,Drug Discovery ,Cellular-uptake ,Humans ,Polylysine ,Molecular Biology ,Nucleic acid analogue ,chemistry.chemical_classification ,Carrier, cellular-uptake, nucleopeptides, peptide nucleic acids, RNA ,Drug Carriers ,Peptide nucleic acid ,Chemistry ,Circular Dichroism ,Organic Chemistry ,Cationic polymerization ,Temperature ,RNA ,Nucleic Acid Hybridization ,Combinatorial chemistry ,Amino acid ,Nucleopeptide ,030104 developmental biology ,Membrane ,Solubility ,Nucleic acid ,Molecular Medicine ,Nucleic Acid Conformation ,Carrier ,Thymine - Abstract
Cationic nucleopeptides belong to a family of synthetic oligomers composed by amino acids and nucleobases. Their capability to recognize nucleic acid targets and to cross cellular membranes provided the basis for considering them as novel non-covalent delivery agents for nucleic acid pharmaceuticals. Herein, starting from a 12-mer nucleopeptide model, the number of cationic residues was modulated in order to obtain new nucleopeptides endowed with high solubility in acqueous medium, acceptable bio-stability, low cytotoxicity and good capability to bind nucleic acid. Two candidates were selected to further investigate their potential as nucleic acid carriers, showing higher efficiency to deliver PNA in comparison with RNA. Noteworthy, this study encourages the development of nucleopeptides as new carriers to extend the known strategies for those nucleic acid analogues, especially PNA, that still remain difficult to drive into the cells.
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- 2018
43. SIRT6 interacts with TRF2 and promotes its degradation in response to DNA damage
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Ettore Novellino, Angela Capolupo, Marcella Mottolese, Angela Maria Rizzo, Carmen D'Angelo, Eric Gilson, Erica Salvati, Salvatore Di Maro, Annamaria Biroccio, Carmen Maresca, Sandro Cosconati, Carla Azzurra Amoreo, Delphine Benarroch-Popivker, Sara Iachettini, Pasquale Zizza, Federica del Gaudio, Isabella Sperduti, Francesco Merlino, Rizzo, A., Iachettini, S., Salvati, E., Zizza, P., Maresca, C., D'Angelo, C., Benarroch-Popivker, D., Capolupo, A., Del Gaudio, F., Cosconati, S., Di Maro, S., Merlino, F., Novellino, E., Amoreo, C. A., Mottolese, M., Sperduti, I., Gilson, E., Biroccio, A., Rizzo, Angela, Iachettini, Sara, Salvati, Erica, Zizza, Pasquale, Maresca, Carmen, D'Angelo, Carmen, Benarroch Popivker, Delphine, Capolupo, Angela, Del Gaudio, Federica, Cosconati, Sandro, DI MARO, Salvatore, Merlino, Francesco, Novellino, Ettore, Amoreo, Carla Azzurra, Mottolese, Marcella, Sperduti, Isabella, Gilson, Eric, and Biroccio, Annamaria
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0301 basic medicine ,SIRT6 ,Models, Molecular ,sirt6 ,deacetylation ,DNA damage ,Protein Conformation ,Proteolysis ,Recombinant Fusion Proteins ,Mutant ,Colorectal Neoplasm ,TRF2 ,Biology ,Genome Integrity, Repair and Replication ,medicine.disease_cause ,DNA damage response ,Cell Line ,Substrate Specificity ,03 medical and health sciences ,medicine ,Genetics ,Sirtuin ,Humans ,Sirtuins ,Telomeric Repeat Binding Protein 2 ,Proteolysi ,Poly(ADP-ribose) Polymerase ,Gene knockdown ,medicine.diagnostic_test ,Protein Stability ,Ubiquitination ,Acetylation ,Antineoplastic Agents, Phytogenic ,Immunohistochemistry ,Cell biology ,Telomere ,030104 developmental biology ,Camptothecin ,Poly(ADP-ribose) Polymerases ,Carcinogenesis ,Colorectal Neoplasms ,Human ,Recombinant Fusion Protein ,DNA Damage ,Protein Binding - Abstract
Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in telomere maintenance and DNA damage response. Here, we show that TRF2 directly binds SIRT6 in a DNA independent manner and that this interaction is increased upon replication stress. Knockdown of SIRT6 up-regulates TRF2 protein levels and counteracts its down-regulation during DNA damage response, leading to cell survival. Moreover, we report that SIRT6 deactetylates in vivo the TRFH domain of TRF2, which in turn, is ubiquitylated in vivo activating the ubiquitin-dependent proteolysis. Notably, overexpression of the TRF2(cT) mutant failed to be stabilized by SIRT6 depletion, demonstrating that the TRFH domain is required for its post-transcriptional modification. Finally, we report an inverse correlation between SIRT6 and TRF2 protein expression levels in a cohort of colon rectal cancer patients. Taken together our findings describe TRF2 as a novel SIRT6 substrate and demonstrate that acetylation of TRF2 plays a crucial role in the regulation of TRF2 protein stability, thus providing a new route for modulating its expression level during oncogenesis and damage response. Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in telomere maintenance and DNA damage response. Here, we show that TRF2 directly binds SIRT6 in a DNA independent manner and that this interaction is increased upon replication stress. Knockdown of SIRT6 upregulates TRF2 protein levels and counteracts its down-regulation during DNA damage response, leading to cell survival. Moreover, we report that SIRT6 deactetylates in vivo the TRFH domain of TRF2, which in turn, is ubiquitylated in vivo activating the ubiquitin-dependent proteolysis. Notably, overexpression of the TRF2(cT) mutant failed to be stabilized by SIRT6 depletion, demonstrating that the TRFH domain is required for its post-transcriptional modification. Finally, we report an inverse correlation between SIRT6 and TRF2 protein expression levels in a cohort of colon rectal cancer patients. Taken together our findings describe TRF2 as a novel SIRT6 substrate and demonstrate that acetylation of TRF2 plays a crucial role in the regulation of TRF2 protein stability, thus providing a new route for modulating its expression level during oncogenesis and damage response.
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- 2017
44. Exploring the Chemical Space of G-Quadruplex Binders: Discovery of a Novel Chemotype Targeting the Human Telomeric Sequence
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Carmen D'Angelo, Francesco Saverio Di Leva, Chiara Cingolani, Annamaria Biroccio, Andrea Cavalli, Erica Salvati, Bruno Pagano, Claudia Sissi, Sandro Cosconati, Jussara Amato, Odra Pinato, Luciana Marinelli, Pasquale Zizza, Antonio Randazzo, Ettore Novellino, Di Leva, F. S., Zizza, P., Cingolani, C., D'Angelo, C., Pagano, Bruno, Amato, Jussara, Salvati, E., Sissi, C., Pinato, O., Marinelli, Luciana, Cavalli, A., Cosconati, S., Novellino, Ettore, Randazzo, Antonio, Biroccio, A., Di Leva, F, Zizza, P, Cingolani, C, D'Angelo, C, Pagano, B, Amato, J, Salvati, E, Sissi, C, Pinato, O, Marinelli, L, Cavalli, A, Cosconati, Sandro, Novellino, E, Randazzo, A, Francesco Saverio Di Leva, Pasquale Zizza, Chiara Cingolani, Carmen D’Angelo, Bruno Pagano, Jussara Amato, Erica Salvati, Claudia Sissi, Odra Pinato, Luciana Marinelli, Andrea Cavalli, Sandro Cosconati, Ettore Novellino, Antonio Randazzo, and Annamaria Biroccio
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Genetics ,Virtual screening ,Chemistry ,DNA damage ,Antineoplastic Agents ,Sequence (biology) ,Computational biology ,Telomere ,Ligands ,G-quadruplex ,Chemical space ,G-Quadruplexes ,Molecular Docking Simulation ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,Humans ,Molecular Medicine ,Receptor ,G-QUADRUPLEX ,Binding selectivity ,DNA - Abstract
Recent findings have unambiguously demonstrated that DNA G-rich sequences can adopt a G-quadruplex folding in living cells, thus further validating them as crucial targets for anticancer therapy. Herein, to identify new potent G4 binders as antitumor drug candidates, we have targeted a 24-nt G4-forming telomeric sequence employing a receptor-based virtual screening approach. Among the best candidates, in vitro binding experiments allowed identification of three novel G4 ligands. Among them, the best compound features an unprecedented binding selectivity for the human telomeric DNA G-quadruplex with no detectable binding for other G4-forming sequences present at different genomic sites. This behavior correlates with the detected ability to generate DNA damage response in tumor cells at the telomeric level and efficient antiproliferative effect on different tumor cell lines at low micromolar concentrations. © 2013 American Chemical Society.
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- 2013
45. Switchable Protecting Strategy for Solid Phase Synthesis of DNA and RNA Interacting Nucleopeptides
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Sandro Cosconati, Paola Stiuso, Maria Gaglione, Maria Emilia Mercurio, Anna Messere, Angela Chambery, Stefano Tomassi, Rosita Russo, Ettore Novellino, Salvatore Di Maro, Stefania Lama, Mercurio, Me, Tomassi, S, Gaglione, M, Russo, R, Chambery, A, Lama, S, Stiuso, P, Cosconati, S, Novellino, E, Di Maro, S, Messere, A., Mercurio, Maria Emilia, Tomassi, Stefano, Gaglione, Maria, Russo, Rosita, Chambery, Angela, Lama, Stefania, Stiuso, Paola, Cosconati, Sandro, Novellino, Ettore, DI MARO, Salvatore, and Messere, Anna
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Sequence (biology) ,010402 general chemistry ,01 natural sciences ,solid phase peptide synthesis ,Nucleobase ,chemistry.chemical_compound ,Solid-phase synthesis ,Cell Line, Tumor ,Protective group ,Humans ,Amino Acid Sequence ,Peptide sequence ,Solid-Phase Synthesis Techniques ,010405 organic chemistry ,Circular Dichroism ,Organic Chemistry ,Nuclear Proteins ,RNA ,DNA ,Combinatorial chemistry ,0104 chemical sciences ,Nucleopeptide ,Biochemistry ,chemistry ,Nucleic acid ,Chemical stability ,Peptides - Abstract
Nucleopeptides are promising nucleic acid mimetics in which the peptide backbone bears nucleobases. They can recognize DNA and RNA targets modulating their biological functions. To date, the lack of an effective strategy for the synthesis of nucleopeptides prevents their evaluation for biological and biomedical applications. Herein, we describe an unprecedented approach that enables the synthesis of cationic both homo and heterosequence nucleopeptides wholly on solid support with high yield and purity. Spectroscopic studies indicate advantageous properties of the nucleopeptides in terms of binding, thermodynamic stability and sequence specific recognition. Biostability assay and laser scanning confocal microscopy analyses reveal that the nucleopeptides feature acceptable serum stability and ability to cross the cell membrane.
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- 2016
46. From the Pharmacophore to the Homology Model of the Benzodiazepine Receptor: The Indolyglyoxylamides Affair
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Ettore Novellino, Barbara Cosimelli, Sandro Cosconati, Luciana Marinelli, Giovanni Greco, Cosimelli, B, Cosconati, Sandro, Marinelli, L, Novellino, E, Greco, G., Cosimelli, Barbara, Cosconati, S., Marinelli, Luciana, Novellino, Ettore, and Greco, Giovanni
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Models, Molecular ,Indoles ,medicine.drug_class ,Stereochemistry ,benzodiazepine receptor ligand ,Ligands ,Docking ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Humans ,Hypnotics and Sedatives ,Structure–activity relationship ,GABA-A Receptor Agonists ,GABA-A Receptor Antagonists ,Homology modeling ,Binding site ,Receptor ,Indole test ,Benzodiazepine ,Binding Sites ,Pharmacophore ,Chemistry ,Brain ,Glyoxylates ,Benzodiazepine receptor ,General Medicine ,Receptors, GABA-A ,Amides ,Protein Subunits ,Anti-Anxiety Agents ,Docking (molecular) ,Homology modelling ,Molecular modelling ,indolyglyoxylamides ,Protein Binding ,Binding mode - Abstract
Interaction between the so-called benzodiazepine receptor (BzR) and the chemically heterogeneous class of its ligands is still one of the most challenging objects of theoretical studies. In the mid-90s our group began to collaborate with Prof. Antonio Da Settimo and coworkers to a project of synthesis and biological evaluation of indolylglyoxylamides designed as BzR ligands. Herein we review our efforts in designing these compounds and in interpreting their structure-affinity relationships. Our investigations were carried out for years by adopting the pharmacophore/topological model for BzR ligands set up by Cook's group. In an attempt to rationalize some puzzling structure-affinity relationships we speculated in 1998 that our ligands interact with the BzR by assuming one of two alternative binding modes (called "A" and "B") depending on whether or not they were substituted at the 5-position of the indole nucleus. Such a model received support from a considerable amount of experimental data accumulated throughout our researches. About a decade later, docking calculations performed on a homology-built model of the α 1 BzR subtype were found in agreement with the hypothesis of mode A and mode B of binding accessible to 5-H and, respectively, 5-Cl/NO 2 indole derivatives. © 2012 Bentham Science Publishers.
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- 2012
47. Sampling protein motion and solvent effect during ligand binding
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Luciana Marinelli, Concettina La Motta, L. Mugnaini, Michele Parrinello, Vittorio Limongelli, Stefania Sartini, Ettore Novellino, Federico Da Settimo, Sandro Cosconati, Limongelli, V, Marinelli, L, Cosconati, Sandro, La Motta, C, Sartini, S, Mugnaini, L, Da Settimo, F, Novellino, E, Parrinello, M., Limongelli, Vittorio, Marinelli, Luciana, Cosconati, S., Motta, C. L., Sartini, S., Mugnaini, L., Settimo, F. D., and Novellino, E.
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Models, Molecular ,ADA ∣ well-tempered metadynamics ∣ ligand/protein docking ∣ path collective variables ∣ reweighting algorithm ,Well-tempered metadynamic ,Molecular dynamics ,Ligands ,010402 general chemistry ,01 natural sciences ,Molecular recognition ,Computational chemistry ,0103 physical sciences ,Multidisciplinary ,Ligand/protein docking ,010304 chemical physics ,Chemistry ,Solvation ,Metadynamics ,Proteins ,Reweighting algorithm ,Biological Sciences ,Ligand (biochemistry) ,0104 chemical sciences ,ADA ,Docking (molecular) ,Biological target ,Solvents ,Solvent effects ,Adenosine deaminase inhibitors ,Algorithms ,Protein Binding ,Path collective variable - Abstract
An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5- a ]pyrimidin-7-one.
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- 2012
48. Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: A first round of lead optimization
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Valeria La Pietra, Sabrina Taliani, Hideaki Nagase, Elisa Nuti, Robert Visse, Federico Da Settimo, Francesco Saverio Di Leva, Ettore Novellino, Luciana Marinelli, Concettina La Motta, Salvatore Santamaria, Sandro Cosconati, Matteo Morelli, Armando Rossello, F Casalini, Isabella Pugliesi, La Pietra, V, Marinelli, L, Cosconati, Sandro, Di Leva, F, Nuti, E, Santamaria, S, Pugliesi, I, Morelli, M, Casalini, F, Rossello, A, La Motta, C, Taliani, S, Visse, R, Nagase, H, da Settimo, F, Novellino, E., LA PIETRA, Valeria, Marinelli, Luciana, Cosconati, S., Di Leva, Francesco Saverio, Nuti, E., Santamaria, S., Pugliesi, I., Morelli, M., Casalini, F., Rossello, A., La Motta, C., Taliani, S., Visse, R., Nagase, H., da Settimo, F., and Novellino, Ettore
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Virtual screening ,High selectivity ,Drug Evaluation, Preclinical ,Nanotechnology ,Articular cartilage ,Osteoarthritis ,Matrix Metalloproteinase Inhibitors ,Matrix metalloproteinase ,Crystallography, X-Ray ,Inhibitory Concentration 50 ,User-Computer Interface ,Catalytic Domain ,Matrix Metalloproteinase 13 ,Drug Discovery ,medicine ,Humans ,Protease Inhibitors ,IC50 ,Cancer ,Pharmacology ,MMP ,Chemistry ,Cartilage ,Organic Chemistry ,General Medicine ,medicine.disease ,medicine.anatomical_structure ,Docking (molecular) ,Drug Design ,Molecular docking ,Cancer research ,Osteoarthriti - Abstract
Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC 50 in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold. © 2011 Elsevier Masson SAS. All rights reserved.
- Published
- 2012
49. Increasing αvβ3 Selectivity of the Anti-Angiogenic Drug Cilengitide by N-Methylation
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Sandro Cosconati, Lucas Doedens, Andreas O. Frank, Ettore Novellino, Luciana Marinelli, Johannes G. Beck, Horst Kessler, Carlos Mas-Moruno, Mas Moruno, C, Beck, Jg, Doedens, L, Frank, Ao, Marinelli, L, Cosconati, Sandro, Novellino, E, Kessler, H., Mas Moruno, C., Beck, J. G., Doedens, L., Frank, A. O., Marinelli, Luciana, Cosconati, S., Novellino, Ettore, and Universitat Politècnica de Catalunya. Departament de Ciència dels Materials i Enginyeria Metal·lúrgica
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Protein Conformation ,integrin ,education ,Integrin ,Angiogenesis Inhibitors ,Cilengitide ,Molecular Dynamics Simulation ,Enginyeria dels materials [Àrees temàtiques de la UPC] ,Methylation ,Peptides, Cyclic ,Catalysis ,cyclic peptide ,Structure-Activity Relationship ,chemistry.chemical_compound ,Protein structure ,Peptide Library ,Structure–activity relationship ,Peptide bond ,Receptors, Vitronectin ,Drugs--Design ,skin and connective tissue diseases ,Peptide library ,Nuclear Magnetic Resonance, Biomolecular ,Medicaments -- Disseny ,biology ,Chemistry ,receptor selectivity ,cyclic peptides ,General Chemistry ,N-methylation ,Integrin alphaVbeta3 ,Biochemistry ,conformational studie ,Cancer research ,biology.protein ,conformational studies ,sense organs ,Selectivity ,psychological phenomena and processes ,Snake Venoms - Abstract
Thumbnail image of graphical abstract A subtle change: Structural changes upon amide bond methylation improve the selectivity of the anti-angiogenic drug Cilengitide, which after N-methylation at distinct positions discriminates between the closely related pro-angiogenic integrins avß3 and avß5 (see scheme).
- Published
- 2011
50. Homology Modeling of NR2B Modulatory Domain of NMDA Receptor and Analysis of Ifenprodil Binding
- Author
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Vittorio Limongelli, Thomas Steinbrecher, David A. Case, Ettore Novellino, Alessia Bertamino, Sandro Cosconati, Luciana Marinelli, Marinelli, L, Cosconati, Sandro, Steinbrecher, T, Limongelli, V, Bertamino, A, Novellino, E, Case, Da, Marinelli, Luciana, Cosconati, S, Limongelli, Vittorio, and Novellino, Ettore
- Subjects
Models, Molecular ,Homology modeling ,Ifenprodil ,Molecular modeling ,NMDA receptors ,NR2B modulatory domain ,Amino Acid Sequence ,Animals ,Excitatory Amino Acid Antagonists ,Humans ,Molecular Sequence Data ,Piperidines ,Protein Binding ,Rats ,Receptors, N-Methyl-D-Aspartate ,Sequence Homology, Amino Acid ,Pharmacology, Toxicology and Pharmaceutics (all) ,Organic Chemistry ,Molecular Medicine ,Stereochemistry ,Toxicology and Pharmaceutics (all) ,Allosteric regulation ,Sequence Homology ,Plasma protein binding ,Biochemistry ,chemistry.chemical_compound ,Models ,Receptors ,Drug Discovery ,General Pharmacology, Toxicology and Pharmaceutics ,Ion channel ,Pharmacology ,Rational design ,Molecular ,NMDA receptor ,Amino Acid ,nervous system ,chemistry ,Docking (molecular) ,Synaptic plasticity ,Neuroscience ,N-Methyl-D-Aspartate - Abstract
NMDA receptors are glutamate-gated ion channels (iGluRs) that are involved in several important physiological functions such as neuronal development, synaptic plasticity, learning, and memory. Among iGluRs, NMDA receptors have been perhaps the most actively investigated for their role in chronic neurodegeneration such as Alzheimer's, Parkinson's, and Huntington's diseases. Recent studies have shown that the NTD of subunit NR2B modulates ion channel gating through the binding of allosteric modulators such as the prototypical compound ifenprodil. In the present paper, the construction of a three-dimensional model for the NR2B modulatory domain is described and docking calculations allow, for the first time, definition of the ifenprodil binding pose at an atomic level and fully explain all the available structure-activity relationships. Moreover, in an attempt to add further insight into the ifenprodil mechanism of action, as it is not completely clear if it binds and stabilizes an open or a closed conformation of the NR2B modulatory domain, a matter, which is fundamental for the rational design of NMDA antagonists, MD simulations followed by an MM-PBSA analysis were performed. These calculations reveal that the closed conformation of the R1-R2 domain, rather than the open, constitutes the high affinity binding site for ifenprodil and that a profound stabilization of the closed conformation upon ifenprodil binding occurs. Thus, for a rational design and/or for virtual screening experiments, the closed conformation of the R1-R2 domain should be taken into account and our 3D model can provide valuable hints for the design of NR2B-selective antagonists. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.
- Published
- 2007
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