12 results on '"David P. Rotella"'
Search Results
2. Expression, purification, and inhibition profile of dihydrofolate reductase from the filarial nematode Wuchereria bancrofti.
- Author
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Andrew M Tobias, Dea Toska, Keith Lange, Tyler Eck, Rohit Bhat, Cheryl A Janson, David P Rotella, Ueli Gubler, and Nina M Goodey
- Subjects
Medicine ,Science - Abstract
Filariasis is a tropical disease caused by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. Known inhibitors of dihydrofolate reductase (DHFR) have been previously shown to kill Brugia malayi nematodes and to inhibit Brugia malayi DHFR (BmDHFR) at nanomolar concentrations. These data suggest that BmDHFR is a potential target for the treatment of filariasis. Here, protocols for cloning, expression and purification of Wuchereria bancrofti DHFR (WbDHFR) were developed. The Uniprot entry J9F199-1 predicts a 172 amino acid protein for WbDHFR but alignment of this sequence to the previously described BmDHFR shows that this WbDHFR sequence lacks a crucial, conserved 13 amino acid loop. The presence of the loop in WbDHFR is supported by a noncanonical splicing event and the loop sequence was therefore included in the gene design. Subsequently, the KM for dihydrofolate (3.7 ± 2 μM), kcat (7.4 ± 0.6 s-1), and pH dependence of activity were determined. IC50 values of methotrexate, trimethoprim, pyrimethamine, raltitrexed, aminopterin, (-)-epicatechin gallate, (-)-epicatechin, and vitexin were measured for WbDHFR and BmDHFR. Methotrexate and structurally related aminopterin were found to be effective inhibitors of WbDHFR, with an KI of 1.2 ± 0.2 nM and 2.1 ± 0.5 nM, respectively, suggesting that repurposing of known antifolate compound may be an effective strategy to treating filariasis. Most compounds showed similar inhibition profiles toward both enzymes, suggesting that the two enzymes have important similarities in their active site environments and can be targeted with the same compound, once a successful inhibitor is identified.
- Published
- 2018
- Full Text
- View/download PDF
3. Analogue-based Drug Discovery III
- Author
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János Fischer, C. Robin Ganellin, David P. Rotella, János Fischer, C. Robin Ganellin, David P. Rotella and János Fischer, C. Robin Ganellin, David P. Rotella, János Fischer, C. Robin Ganellin, David P. Rotella
- Published
- 2012
4. Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase
- Author
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Tyler Eck, John Gordon, Wayne E. Childers, Brandon S. Pybus, Dennis J. Colussi, Tamara Kreiss, Alison Roth, Rammohan R. Yadav Bheemanaboina, David P. Rotella, Shams Ul Mahmood, Patricia J. Lee, Purnima Bhanot, Samantha O. Aylor, Mariana Laureano de Souza, Mariana Lozano Gonzalez, and John J. Siekierka
- Subjects
Cellular activity ,biology ,medicine.drug_class ,Organic Chemistry ,Plasmodium falciparum ,Protein kinase inhibitor ,Pharmacology ,medicine.disease ,biology.organism_classification ,Biochemistry ,chemistry.chemical_compound ,chemistry ,parasitic diseases ,Drug Discovery ,medicine ,Imidazole ,cGMP-dependent protein kinase ,Malaria - Abstract
[Image: see text] The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure–activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiple Plasmodium species that appears to be correlated with the in vitro potency.
- Published
- 2021
5. Plasmodium falciparum cGMP-Dependent Protein Kinase – A Novel Chemotherapeutic Target
- Author
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David P. Rotella, John J. Siekierka, and Purnima Bhanot
- Subjects
Microbiology (medical) ,Plasmodium ,kinase ,Mini Review ,lcsh:QR1-502 ,malaria ,Pharmacology ,Microbiology ,lcsh:Microbiology ,03 medical and health sciences ,parasitic diseases ,Plasmodium berghei ,Protein kinase A ,030304 developmental biology ,0303 health sciences ,biology ,030306 microbiology ,Effector ,Kinase ,Plasmodium falciparum ,biology.organism_classification ,second messenger ,Second messenger system ,cGMP signaling ,cGMP-dependent protein kinase - Abstract
The primary effector of cGMP signaling in Plasmodium is the cGMP-dependent protein kinase (PKG). Work in human-infective Plasmodium falciparum and rodent-infective Plasmodium berghei has provided biological validation of P. falciparum PKG (PfPKG) as a drug target for treating and/or protecting against malaria. PfPKG is essential in the asexual erythrocytic and sexual cycles as well as the pre-erythrocytic cycle. Medicinal chemistry efforts, both target-based and phenotype-based, have targeted PfPKG in the past few years. This review provides a brief overview of their results and challenges.
- Published
- 2021
6. The spectral properties of (-)-epigallocatechin 3-O-gallate (EGCG) fluorescence in different solvents: dependence on solvent polarity.
- Author
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Vladislav Snitsarev, Michael N Young, Ross M S Miller, and David P Rotella
- Subjects
Medicine ,Science - Abstract
(-)-Epigallocatechin 3-O-gallate (EGCG) a molecule found in green tea and known for a plethora of bioactive properties is an inhibitor of heat shock protein 90 (HSP90), a protein of interest as a target for cancer and neuroprotection. Determination of the spectral properties of EGCG fluorescence in environments similar to those of binding sites found in proteins provides an important tool to directly study protein-EGCG interactions. The goal of this study is to examine the spectral properties of EGCG fluorescence in an aqueous buffer (AB) at pH=7.0, acetonitrile (AN) (a polar aprotic solvent), dimethylsulfoxide (DMSO) (a polar aprotic solvent), and ethanol (EtOH) (a polar protic solvent). We demonstrate that EGCG is a highly fluorescent molecule when excited at approximately 275 nm with emission maxima between 350 and 400 nm depending on solvent. Another smaller excitation peak was found when EGCG is excited at approximately 235 nm with maximum emission between 340 and 400 nm. We found that the fluorescence intensity (FI) of EGCG in AB at pH=7.0 is significantly quenched, and that it is about 85 times higher in an aprotic solvent DMSO. The Stokes shifts of EGCG fluorescence were determined by solvent polarity. In addition, while the emission maxima of EGCG fluorescence in AB, DMSO, and EtOH follow the Lippert-Mataga equation, its fluorescence in AN points to non-specific solvent effects on EGCG fluorescence. We conclude that significant solvent-dependent changes in both fluorescence intensity and fluorescence emission shifts can be effectively used to distinguish EGCG in aqueous solutions from EGCG in environments of different polarity, and, thus, can be used to study specific EGCG binding to protein binding sites where the environment is often different from aqueous in terms of polarity.
- Published
- 2013
- Full Text
- View/download PDF
7. Discovery of isoxazolyl-based inhibitors of Plasmodium falciparum cGMP-dependent protein kinase
- Author
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Rammohan R. Yadav Bheemanaboina, Huimin Cheng, Agnieska Chojnowski, Tyler Eck, David P. Rotella, Ramappa Chakrasali, Sreedhar R. Tummalapalli, John J. Siekierka, Tamara Kreiss, and Shams Ul Mahmood
- Subjects
Pharmaceutical Science ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,parasitic diseases ,medicine ,Parasite hosting ,Antimalarial Agent ,Protein kinase A ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,Organic Chemistry ,Plasmodium falciparum ,medicine.disease ,biology.organism_classification ,Chemistry ,Enzyme ,chemistry ,030220 oncology & carcinogenesis ,Molecular Medicine ,cGMP-dependent protein kinase ,Malaria - Abstract
The cGMP-dependent protein kinase in Plasmodium falciparum (PfPKG) plays multiple roles in the life cycle of the parasite. As a result, this enzyme is a potential target for new antimalarial agents. Existing inhbitors, while potent and active in malaria models are not optimal. This communication describes initial optimization of a structurally distinct class of PfPKG inhibitors.
- Published
- 2019
8. Expression, purification, and inhibition profile of dihydrofolate reductase from the filarial nematode Wuchereria bancrofti
- Author
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Cheryl A. Janson, Keith Richard Lange, Dea Toska, Andrew M. Tobias, David P. Rotella, Nina M. Goodey, Tyler Eck, Rohit Bhat, and Ueli Gubler
- Subjects
0301 basic medicine ,Nematoda ,lcsh:Medicine ,Protein Sequencing ,medicine.disease_cause ,Brugia malayi ,Database and Informatics Methods ,chemistry.chemical_compound ,Dihydrofolate reductase ,Medicine and Health Sciences ,Cloning, Molecular ,Enzyme Inhibitors ,Brugia Malayi ,lcsh:Science ,Peptide sequence ,chemistry.chemical_classification ,Multidisciplinary ,biology ,Organic Compounds ,Chemistry ,Drugs ,Eukaryota ,Filariasis ,Pyrimethamine ,Wuchereria bancrofti ,Helminth Infections ,Physical Sciences ,Antifolate ,Sequence Analysis ,Wuchereria ,Research Article ,medicine.drug ,Bioinformatics ,Research and Analysis Methods ,Aminopterin ,Gene Expression Regulation, Enzymologic ,Antimalarials ,03 medical and health sciences ,parasitic diseases ,Parasitic Diseases ,Brugia ,medicine ,Animals ,Amino Acid Sequence ,Molecular Biology Techniques ,Sequencing Techniques ,Molecular Biology ,Imidazole ,Flavonoids ,Pharmacology ,030102 biochemistry & molecular biology ,Organic Chemistry ,lcsh:R ,Organisms ,Chemical Compounds ,Biology and Life Sciences ,biology.organism_classification ,Invertebrates ,Molecular biology ,Tetrahydrofolate Dehydrogenase ,Methotrexate ,030104 developmental biology ,Enzyme ,biology.protein ,lcsh:Q ,Sequence Alignment - Abstract
Filariasis is a tropical disease caused by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. Known inhibitors of dihydrofolate reductase (DHFR) have been previously shown to kill Brugia malayi nematodes and to inhibit Brugia malayi DHFR (BmDHFR) at nanomolar concentrations. These data suggest that BmDHFR is a potential target for the treatment of filariasis. Here, protocols for cloning, expression and purification of Wuchereria bancrofti DHFR (WbDHFR) were developed. The Uniprot entry J9F199-1 predicts a 172 amino acid protein for WbDHFR but alignment of this sequence to the previously described BmDHFR shows that this WbDHFR sequence lacks a crucial, conserved 13 amino acid loop. The presence of the loop in WbDHFR is supported by a noncanonical splicing event and the loop sequence was therefore included in the gene design. Subsequently, the KM for dihydrofolate (3.7 ± 2 μM), kcat (7.4 ± 0.6 s-1), and pH dependence of activity were determined. IC50 values of methotrexate, trimethoprim, pyrimethamine, raltitrexed, aminopterin, (-)-epicatechin gallate, (-)-epicatechin, and vitexin were measured for WbDHFR and BmDHFR. Methotrexate and structurally related aminopterin were found to be effective inhibitors of WbDHFR, with an KI of 1.2 ± 0.2 nM and 2.1 ± 0.5 nM, respectively, suggesting that repurposing of known antifolate compound may be an effective strategy to treating filariasis. Most compounds showed similar inhibition profiles toward both enzymes, suggesting that the two enzymes have important similarities in their active site environments and can be targeted with the same compound, once a successful inhibitor is identified.
- Published
- 2018
9. Analogue-based Drug Discovery III
- Author
-
János Fischer, C. Robin Ganellin, David P. Rotella, János Fischer, C. Robin Ganellin, and David P. Rotella
- Subjects
- Drugs--Design, Drug development
- Abstract
Most drugs are analogue drugs. There are no general rules how a new drug can be discovered, nevertheless, there are some observations which help to find a new drug, and also an individual story of a drug discovery can initiate and help new discoveries. Volume III is a continuation of the successful book series with new examples of established and recently introduced drugs. The major part of the book is written by key inventors either as a case study or a study of an analogue class. With its wide range across a variety of therapeutic fields and chemical classes, this is of interest to virtually every researcher in drug discovery and pharmaceutical chemistry, and -- together with the previous volumes -- constitutes the first systematic approach to drug analogue development.
- Published
- 2013
10. Structure–activity studies of (−)-epigallocatechin gallate derivatives as HCV entry inhibitors
- Author
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Rohit Bhat, Karin Séron, Gaspard Deloison, Yves Rouillé, David P. Rotella, Jungeun Jasmine Lee, Amna T. Adam, Montclair State University, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), This research was supported by the Margaret and Herman Sokol Endowment, Montclair State University and the Sokol Institute for Pharmaceutical Life Sciences. HCV research conducted by the authors is supported by the French ‘Agence Nationale de Recherche sur le Sida et les hépatites virales’ (ANRS) and BioImaging Center by a grant ANR-10-EQPX-04-01., We thank T. Wakita for providing essential reagents. We thank Jean Dubuisson, Priscille Brodin and Frank Lafont for helpful discussion., Montclair State University [USA] (MSU), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Cell Survival ,Hepatitis C virus ,[SDV]Life Sciences [q-bio] ,Clinical Biochemistry ,Pharmaceutical Science ,Hepacivirus ,Microbial Sensitivity Tests ,Pharmacology ,Epigallocatechin gallate ,medicine.disease_cause ,Biochemistry ,Antiviral Agents ,complex mixtures ,Catechin ,Natural product ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,Viral entry ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Potency ,Humans ,heterocyclic compounds ,Antiviral ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,food and beverages ,Biological activity ,Stereoisomerism ,Gallate ,Virus Internalization ,3. Good health ,chemistry ,HCV entry ,Cell culture ,030220 oncology & carcinogenesis ,Molecular Medicine ,sense organs - Abstract
International audience; Preventing viral entry into cells is a recognized approach for HIV therapy and has attracted attention for use against the hepatitis C virus (HCV). Recent reports described the activity of (−)-epigallocatechin gallate (EGCG) as an inhibitor of HCV entry with modest potency. EGCG is a polyphenolic natural product with a wide range of biological activity and unfavorable pharmaceutical properties. In an attempt to identify more drug-like EGCG derivatives with improved efficacy as HCV entry inhibitors, we initiated structure–activity investigations using semi-synthetic and synthetic EGCG analogs. The data show that there are multiple regions in the EGCG structure that contribute to activity. The gallate ester portion of the molecule appears to be of particular importance as a 3,4-difluoro analog of EGCG enhanced potency. This derivative and other active compounds were shown not to be cytotoxic in Huh-7 cell culture. These data suggest that more potent, non-cytotoxic EGCG analogs can be prepared in an attempt to identify more drug-like candidates to treat HCV infection by this mechanism.
- Published
- 2014
11. Gamma Secretase Modulators
- Author
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David P. Rotella
- Subjects
Chemistry ,Organic Chemistry ,Neurodegeneration ,Aβ peptide ,Druggability ,Erythropoietin-producing hepatocellular (Eph) receptor ,Pharmacology ,medicine.disease ,Biochemistry ,Disease area ,Aspartate protease ,Biological target ,Drug Discovery ,medicine ,Gamma secretase - Abstract
Notes The authors declare no competing financial interest. Title: Gamma Secretase Modulators Application Number: WO 2013066740A1 Publication date: 10 May 2013 Priority Application: 61/553,384 Priority date: 31 October 2011 Inventors: W. Greenlee, D. Pissarnitski, Z. Zhao, Z. Zhu Assignee Company: Merck Sharpe & Dohme Disease Area: Neurodegeneration Biological Target: Gamma secretase Summary: Gamma secretase is an aspartic protease complex involved in the biosynthesis of Aβ peptide, a potential neurotoxic contributor in the progression of Alzheimer’s disease. Direct inhibition of enzymatic activity introduces potential selectivity issues associated with other biological functions of gamma secretase including Notch and Eph processing. As an alternative approach to gamma secretase inhibition, modulation of enzyme activity using, e.g., NSAIDs is a potentially druggable concept. This patent describes the synthesis and evaluation of a novel chemical series that demonstrates inhibition of gamma secretase activity in vitro and reduction of Aβ42 CSF levels following oral administration of a standard dose of 30 mg/kg. Primary Markush
- Published
- 2013
12. Imidazotriazinone Compounds: Patent Highlight
- Author
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David P. Rotella
- Subjects
Information retrieval ,Text mining ,business.industry ,Organic Chemistry ,Drug Discovery ,Medicine ,business ,Biochemistry ,Data science - Published
- 2012
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