113 results on '"Spiros Liras"'
Search Results
2. Donated chemical probes for open science
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Susanne Müller, Suzanne Ackloo, Cheryl H Arrowsmith, Marcus Bauser, Jeremy L Baryza, Julian Blagg, Jark Böttcher, Chas Bountra, Peter J Brown, Mark E Bunnage, Adrian J Carter, David Damerell, Volker Dötsch, David H Drewry, Aled M Edwards, James Edwards, Jon M Elkins, Christian Fischer, Stephen V Frye, Andreas Gollner, Charles E Grimshaw, Adriaan IJzerman, Thomas Hanke, Ingo V Hartung, Steve Hitchcock, Trevor Howe, Terry V Hughes, Stefan Laufer, Volkhart MJ Li, Spiros Liras, Brian D Marsden, Hisanori Matsui, John Mathias, Ronan C O'Hagan, Dafydd R Owen, Vineet Pande, Daniel Rauh, Saul H Rosenberg, Bryan L Roth, Natalie S Schneider, Cora Scholten, Kumar Singh Saikatendu, Anton Simeonov, Masayuki Takizawa, Chris Tse, Paul R Thompson, Daniel K Treiber, Amélia YI Viana, Carrow I Wells, Timothy M Willson, William J Zuercher, Stefan Knapp, and Anke Mueller-Fahrnow
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Chemical probes ,Target validation ,Open Science ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project.
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- 2018
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- View/download PDF
3. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain.
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Nathanael G Lintner, Kim F McClure, Donna Petersen, Allyn T Londregan, David W Piotrowski, Liuqing Wei, Jun Xiao, Michael Bolt, Paula M Loria, Bruce Maguire, Kieran F Geoghegan, Austin Huang, Tim Rolph, Spiros Liras, Jennifer A Doudna, Robert G Dullea, and Jamie H D Cate
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Biology (General) ,QH301-705.5 - Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome that allows small molecules to specifically block translation of individual transcripts.
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- 2017
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4. PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease
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Ariamala Gopalsamy, Ann E. Aulabaugh, Amey Barakat, Kevin C. Beaumont, Shawn Cabral, Daniel P. Canterbury, Agustin Casimiro-Garcia, Jeanne S. Chang, Ming Z. Chen, Chulho Choi, Robert L. Dow, Olugbeminiyi O. Fadeyi, Xidong Feng, Scott P. France, Roger M. Howard, Jay M. Janz, Jayasankar Jasti, Reema Jasuja, Lyn H. Jones, Amanda King-Ahmad, Kelly M. Knee, Jeffrey T. Kohrt, Chris Limberakis, Spiros Liras, Carlos A. Martinez, Kim F. McClure, Arjun Narayanan, Jatin Narula, Jonathan J. Novak, Thomas N. O’Connell, Mihir D. Parikh, David W. Piotrowski, Olga Plotnikova, Ralph P. Robinson, Parag V. Sahasrabudhe, Raman Sharma, Benjamin A. Thuma, Dipy Vasa, Liuqing Wei, A. Zane Wenzel, Jane M. Withka, Jun Xiao, and Hatice G. Yayla
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Hemolytic anemia ,Erythrocytes ,Chemistry ,Point mutation ,Hemoglobin, Sickle ,Cell ,Genetic disorder ,Phases of clinical research ,Hemoglobin A ,Anemia, Sickle Cell ,Disease ,Pharmacology ,Multiple dose ,medicine.disease ,Oxygen ,Mice ,medicine.anatomical_structure ,Drug Discovery ,Quinolines ,medicine ,Animals ,Molecular Medicine ,Hemoglobin - Abstract
Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.
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- 2020
5. Use of 3D Properties to Characterize Beyond Rule-of-5 Property Space for Passive Permeation.
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Cristiano R. W. Guimarães, Alan M. Mathiowetz, Marina Shalaeva, Gilles Goetz, and Spiros Liras
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- 2012
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6. Exploring Aromatic Chemical Space with NEAT: Novel and Electronically Equivalent Aromatic Template.
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Meihua Tu, Brajesh K. Rai, Alan M. Mathiowetz, Mary Didiuk, Jeffrey A. Pfefferkorn, Angel Guzman-Perez, John Benbow, Cristiano R. W. Guimarães, Scot Mente, Matthew M. Hayward, and Spiros Liras
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- 2012
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7. Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase Inhibitors through Liver Targeting
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Shawn D. Doran, Jana Polivkova, James A. Southers, Scott W. Bagley, Kim Huard, Dilinie P. Fernando, Manthena V.S. Varma, David A. Beebe, David J. Edmonds, Robert L. Dow, Benjamin A. Thuma, Collin Crowley, William P. Esler, Trenton T. Ross, David A. Tess, Mark Niosi, Amit S. Kalgutkar, Jeffrey A. Pfefferkorn, Norimitsu Shirai, David A. Griffith, Shawn Cabral, Andrew H. Smith, Gregg D. Cappon, Vincent Mascitti, Matthew S. Dowling, Andre Shavnya, David Price, Ayman El-Kattan, Aaron C. Smith, Yi-an Bi, Spiros Liras, Xiaojing Helen Yang, and Cathy Préville
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Pharmacology ,01 natural sciences ,Substrate Specificity ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Delivery Systems ,Non-alcoholic Fatty Liver Disease ,Drug Discovery ,medicine ,Animals ,Humans ,Platelet ,Enzyme Inhibitors ,Fatty acid synthesis ,030304 developmental biology ,0303 health sciences ,biology ,Lipogenesis ,Acetyl-CoA carboxylase ,Lipid metabolism ,0104 chemical sciences ,Pyruvate carboxylase ,Organic anion-transporting polypeptide ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Liver ,chemistry ,biology.protein ,Molecular Medicine ,Bone marrow ,Acetyl-CoA Carboxylase - Abstract
Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.
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- 2020
8. Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule
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Spiros Liras, Elizabeth Montabana, Wenfei Li, Jamie H. D. Cate, Kim F. McClure, Stacey Tsai-Lan Chang, Robert Dullea, and Fred R. Ward
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Models, Molecular ,Peptidyl transferase ,Polypeptide chain ,Heterocyclic Compounds, 4 or More Rings ,Ribosome ,Article ,03 medical and health sciences ,0302 clinical medicine ,Chain (algebraic topology) ,RNA, Transfer ,Structural Biology ,Translation elongation ,Protein biosynthesis ,Humans ,Molecule ,RNA, Messenger ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Messenger RNA ,biology ,Chemistry ,RNA ,Translation (biology) ,Ribosomal RNA ,Small molecule ,Cell biology ,Protein Biosynthesis ,Biophysics ,biology.protein ,Ribosomes ,030217 neurology & neurosurgery ,HeLa Cells - Abstract
Small molecules that target the ribosome generally have a global impact on protein synthesis. However, the drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small subset of proteins by an unknown mechanism. In high-resolution cryo-electron microscopy (cryo-EM) structures of human ribosome nascent chain complexes stalled by PF846, PF846 binds in the ribosome exit tunnel in a newly-identified and eukaryotic-specific pocket formed by the 28S ribosomal RNA (rRNA), and redirects the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state that precedes mRNA and tRNA translocation, with peptidyl-tRNA occupying a mixture of A/A and hybrid A/P sites, in which the tRNA 3’-CCA end is improperly docked in the peptidyl transferase center. Using mRNA libraries, selections of PF846-dependent translation elongation stalling sequences reveal sequence preferences near the peptidyl transferase center, and uncover a newly-identified mechanism by which PF846 selectively blocks translation termination. These results illuminate how a small molecule selectively stalls the translation of the human ribosome, and provides a structural foundation for developing small molecules that inhibit the production of proteins of therapeutic interest.
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- 2019
9. Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents
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Liuqing Wei, Jun Xiao, Joseph S. Warmus, Jeffrey R. Chabot, Robert Dullea, Christopher T. Salatto, David W. Piotrowski, Benjamin A. Thuma, Donna N. Petersen, Chris Limberakis, Julien Genovino, Steven B. Coffey, Michael W. Bolt, Kim F. McClure, Kevin D. Hesp, Spiros Liras, Jamie H. D. Cate, Nathanael G. Lintner, Allyn T. Londregan, Gary Erik Aspnes, and Benjamin Reidich
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Male ,0301 basic medicine ,01 natural sciences ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,03 medical and health sciences ,In vivo ,Drug Discovery ,Animals ,Structure–activity relationship ,Protease Inhibitors ,010405 organic chemistry ,Chemistry ,PCSK9 ,PCSK9 Inhibitors ,Subtilisin ,Hit to lead ,Proprotein convertase ,Small molecule ,Rats ,0104 chemical sciences ,030104 developmental biology ,Biochemistry ,Drug Design ,Molecular Medicine ,Kexin ,Safety - Abstract
The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins.
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- 2018
10. Receptor-Mediated Delivery of CRISPR-Cas9 Endonuclease for Cell-Type-Specific Gene Editing
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Ariana Hirsh, Robert Dullea, Meihua Tu, Spiros Liras, Joan Compte Barrón, Kris A. Borzilleri, Nannan Ma, Rima Mendonsa, Justin Bellenger, Romain Rouet, Lorena de Oñate, Xidong Feng, Jennifer A. Doudna, Nathanael G. Lintner, David M. Rubitski, Benjamin A. Thuma, Marc D. Roy, Alison H. Varghese, Kim F. McClure, Ross C. Wilson, Thomas J. McLellan, Hanna M. Wisniewska, James E. Finley, Boris A. Chrunyk, Vincent Mascitti, Kaihong Zhou, and Kevin D. Hesp
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0301 basic medicine ,Cell ,02 engineering and technology ,Protein Engineering ,Endocytosis ,Biochemistry ,Catalysis ,Cell Line ,03 medical and health sciences ,Endonuclease ,Colloid and Surface Chemistry ,Live cell imaging ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Receptor ,Gene Editing ,Tumor ,5.2 Cellular and gene therapies ,Molecular Structure ,biology ,Chemistry ,Cas9 ,Hep G2 Cells ,General Chemistry ,Receptor-mediated endocytosis ,Endonucleases ,021001 nanoscience & nanotechnology ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Chemical Sciences ,biology.protein ,Asialoglycoprotein receptor ,Generic health relevance ,Development of treatments and therapeutic interventions ,CRISPR-Cas Systems ,0210 nano-technology ,Biotechnology - Abstract
CRISPR-Cas RNA-guided endonucleases hold great promise for disrupting or correcting genomic sequences through site-specific DNA cleavage and repair. However, the lack of methods for cell- and tissue-selective delivery currently limits both research and clinical uses of these enzymes. We report the design and in vitro evaluation of S. pyogenes Cas9 proteins harboring asialoglycoprotein receptor ligands (ASGPrL). In particular, we demonstrate that the resulting ribonucleoproteins (Cas9-ASGPrL RNP) can be engineered to be preferentially internalized into cells expressing the corresponding receptor on their surface. Uptake of such fluorescently labeled proteins in liver-derived cell lines HEPG2 (ASGPr+) and SKHEP (control; diminished ASGPr) was studied by live cell imaging and demonstrates increased accumulation of Cas9-ASGPrL RNP in HEPG2 cells as a result of effective ASGPr-mediated endocytosis. When uptake occurred in the presence of a peptide with endosomolytic properties, we observed receptor-facilitated and cell-type specific gene editing that did not rely on electroporation or the use of transfection reagents. Overall, these in vitro results validate the receptor-mediated delivery of genome-editing enzymes as an approach for cell-selective gene editing and provide a framework for future potential applications to hepatoselective gene editing in vivo.
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- 2018
11. Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis
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Dennis O. Scott, Spiros Liras, Roger B. Ruggeri, Heather Eng, Adam S. Kamlet, Ryosuke Arakawa, David W. Piotrowski, Robert Dullea, Christopher T. Salatto, Karen Atkinson, Michael W. Bolt, Anne-Marie R. Dechert-Schmitt, Paul DaSilva-Jardine, Allyn T. Londregan, Brian Raymer, Kenneth Dahl, Daniel P. Canterbury, Donna N. Petersen, Paula M. Loria, Chris Limberakis, Emi Kimoto, Kim F. McClure, Kevin Beaumont, Liuqing Wei, Akihiro Takano, Kevin P. Maresca, Jun Xiao, Amanda King-Ahmad, Christer Halldin, Benjamin Reidich, and Jeffrey R. Chabot
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0301 basic medicine ,Drug ,media_common.quotation_subject ,Ribosome ,Catalysis ,Small Molecule Libraries ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Humans ,media_common ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,PCSK9 ,PCSK9 Inhibitors ,Subtilisin ,General Medicine ,General Chemistry ,Prodrug ,Proprotein convertase ,Small molecule ,030104 developmental biology ,Liver ,Biochemistry ,030220 oncology & carcinogenesis ,Hepatocytes ,Kexin ,Proprotein Convertase 9 - Abstract
Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18F-isotopologue validated our liver-targeting approach.
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- 2017
12. Helixconstraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta-arrestin 2 signaling
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Paula M. Loria, Aline Dantas de Araujo, David Price, Adam J. Cotterell, David A. Griffith, Spiros Liras, Timothy A. Hill, David P. Fairlie, Weijun Xu, David R. Derksen, Robert V. Stanton, Fabien Plisson, Huy N. Hoang, Justin M. Mitchell, and David J. Edmonds
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Protein Conformation, alpha-Helical ,0301 basic medicine ,medicine.medical_specialty ,Lactams ,medicine.medical_treatment ,Peptide ,Molecular Dynamics Simulation ,01 natural sciences ,Glucagon-Like Peptide-1 Receptor ,03 medical and health sciences ,Glucagon-Like Peptide 1 ,Internal medicine ,Insulin Secretion ,Drug Discovery ,Cyclic AMP ,medicine ,Humans ,Insulin ,Amino Acid Sequence ,Receptor ,Peptide sequence ,Pharmacology ,chemistry.chemical_classification ,010405 organic chemistry ,Activator (genetics) ,Chemistry ,Pancreatic islets ,Organic Chemistry ,General Medicine ,beta-Arrestin 2 ,0104 chemical sciences ,Amino acid ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Amino Acid Substitution ,Biochemistry ,Mutation ,Alpha helix ,Signal Transduction - Abstract
Glucagon-like peptide (GLP-1) is an endogenous hormone that induces insulin secretion from pancreatic islets and modified forms are used to treat diabetes mellitus type 2. Understanding how GLP-1 interacts with its receptor (GLP-1R) can potentially lead to more effective drugs. Modeling and NMR studies of the N-terminus of GLP-1 suggest a β-turn between residues Glu9-Phe12 and a kinked alpha helix between Val16-Gly37. N-terminal turn constraints attenuated binding affinity and activity (compounds 1-8). Lys-Asp (i, i+4) crosslinks in the middle and at the C-terminus increased alpha helicity and cAMP stimulation without much effect on binding affinity or beta-arrestin 2 recruitment (compounds 9-18). Strategic positioning of helix-inducing constraints and amino acid substitutions (Tyr16, Ala22) increased peptide helicity and produced ten-fold higher cAMP potency (compounds 19-28) over GLP-1(7-37)-NH2. The most potent cAMP activator (compound 23) was also the most potent inducer of insulin secretion.
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- 2017
13. Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules
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Alan M. Mathiowetz, Cameron R. Pye, Spiros Liras, R. Scott Lokey, Akihiro Furukawa, Chad E. Townsend, Lyns Etienne, Yongtong Lao, Terra D. Haddad, Chris Limberakis, David Price, Joshua Schwochert, and William M. Hewitt
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0301 basic medicine ,Cell Membrane Permeability ,Membrane permeability ,Molecular mass ,010405 organic chemistry ,Chemistry ,Synthetic membrane ,Nanotechnology ,Permeation ,01 natural sciences ,Article ,0104 chemical sciences ,03 medical and health sciences ,030104 developmental biology ,Adsorption ,Membrane ,Permeability (electromagnetism) ,Chemical physics ,Drug Discovery ,Humans ,Molecular Medicine ,Molecule - Abstract
Macrocyclic peptides are considered large enough to inhibit “undruggable” targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (~800 Da < MW < ~1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models. This observation, corroborated by a set of natural products, helps define criteria for achieving permeability in larger molecular size regimes and suggests an operational cutoff, beyond which passive permeability is constrained by a sharply increasing penalty on membrane permeation.
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- 2017
14. Permeability of Cyclic Peptide Macrocycles and Cyclotides and Their Potential as Therapeutics
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Kim F. McClure and Spiros Liras
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chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Drug discovery ,Organic Chemistry ,Computational biology ,01 natural sciences ,Biochemistry ,Cyclic peptide ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Cyclotides ,Drug Discovery ,Lipinski's rule of five ,Cell permeability - Abstract
[Image: see text] Macrocycles have emerged as a viable approach for the modulation of tough targets in drug discovery. In this Innovations article we discuss recent progress toward the design of cell permeable and orally bioavailable peptide macrocycles and cyclotides and provide a perspective for their potential as therapeutics. We highlight design concepts that may be broadly relevant to drug discovery efforts beyond the rule of five.
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- 2019
15. Studies directed to the total synthesis of biologically active natural products
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Spiros Liras
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Chemistry ,Organic chemistry ,Total synthesis ,Combinatorial chemistry ,Natural (archaeology) - Published
- 2018
16. Discovery of Potent and Selective Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1
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Eddie Yang, Jennifer L. Liras, Christine C. Orozco, Christopher W. am Ende, Matthew A. Movsesian, Jayvardhan Pandit, John M. Humphrey, Stephen Jenkinson, Frank S. Menniti, Thomas Allen Chappie, Spiros Liras, Stacey L. Becker, Felix Vajdos, and Fabrice Vandeput
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0301 basic medicine ,Models, Molecular ,Phosphodiesterase Inhibitors ,Protein Conformation ,030204 cardiovascular system & hematology ,PDE1 ,Human myocardium ,Cocrystal ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Quinazoline ,Ic50 values ,Cyclic AMP ,Humans ,Cyclic nucleotide phosphodiesterase ,Molecular Structure ,Myocardium ,Cyclic Nucleotide Phosphodiesterases, Type 1 ,030104 developmental biology ,chemistry ,Biochemistry ,Plasma concentration ,Quinazolines ,Molecular Medicine - Abstract
We disclose the discovery and X-ray cocrystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor (S)-3 readily attains free plasma concentrations above PDE1 IC50 values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue. These compounds represent promising new tools to probe the value of PDE1 inhibition in the treatment of cardiovascular disease.
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- 2018
17. Receptor‐Mediated Delivery of CRISPR‐Cas9 Endonuclease for Cell Type Specific Gene Editing
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Robert Dullea, Kris A. Borzilleri, Romain Rouet, Vincent Mascitti, Ross C. Wilson, Boris A. Chrunyk, Ariana Hirsh, Benjamin A. Thuma, Xidong Feng, Jennifer A. Doudna, Hanna M. Wisniewska, Spiros Liras, Thomas J. McLellan, Kaihong Zhou, Kim F. McClure, James E. Finley, Joan Compte Barrón, Kevin D. Hesp, Meihua Tu, David M. Rubitski, Lorena de Oñate, Alison H. Varghese, Rima Mendonsa, Nannan Ma, Justin Bellenger, Marc D. Roy, and Nathanael G. Lintner
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Endonuclease ,Genome editing ,biology ,Cell type specific ,Genetics ,biology.protein ,CRISPR ,Receptor-mediated endocytosis ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology - Published
- 2018
18. Author response: Donated chemical probes for open science
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David H. Drewry, Steve Hitchcock, Volker Dötsch, Ingo Hartung, Brian D. Marsden, Hisanori Matsui, C. Bountra, Carrow I. Wells, Marcus Bauser, Stefan Knapp, Volkhart Mj Li, Amélia Yi Viana, Christian Fischer, Mathias John Paul, Adrian Carter, Spiros Liras, Julian Blagg, Mark Edward Bunnage, Suzanne Ackloo, Adriaan P. IJzerman, Susanne Müller, Stephen V. Frye, Saul H Rosenberg, Natalie S Schneider, Daniel K Treiber, Andreas Gollner, David R. Damerell, Cora Scholten, Bryan L. Roth, Cheryl H. Arrowsmith, Charles E. Grimshaw, Aled M. Edwards, Kumar Singh Saikatendu, Timothy M. Willson, Jeremy L Baryza, Thomas Hanke, Masayuki Takizawa, Peter Brown, Terry V Hughes, James P. Edwards, Daniel Rauh, Trevor Howe, Anke Mueller-Fahrnow, Ronan C. O'Hagan, Chris Tse, Vineet Pande, Anton Simeonov, Paul R. Thompson, Dafydd R. Owen, J.M. Elkins, Jark Böttcher, William J. Zuercher, and Stefan Laufer
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Engineering ,Open science ,business.industry ,Library science ,business - Published
- 2018
19. Donated chemical probes for open science
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Julian Blagg, David H. Drewry, Steve Hitchcock, Hisanori Matsui, Carrow I. Wells, Daniel Rauh, Anke Mueller-Fahrnow, Ronan C. O'Hagan, Adriaan P. IJzerman, Kumar Singh Saikatendu, Stefan Laufer, Timothy M. Willson, Paul R. Thompson, Chris Tse, Saul H Rosenberg, C. Bountra, Marcus Bauser, Dafydd R. Owen, Brian D. Marsden, Terry V Hughes, Daniel K Treiber, James P. Edwards, Bryan L. Roth, Cheryl H. Arrowsmith, Suzanne Ackloo, J.M. Elkins, Adrian Carter, Spiros Liras, Stefan Knapp, Christian Fischer, Susanne Müller, Amélia Yi Viana, Mathias John Paul, William J. Zuercher, Masayuki Takizawa, Jeremy L Baryza, Thomas Hanke, Peter Brown, David R. Damerell, Cora Scholten, Stephen V. Frye, Anton Simeonov, Mark Edward Bunnage, Charles E. Grimshaw, Andreas Gollner, Aled M. Edwards, Natalie S Schneider, Trevor Howe, Volker Dötsch, Ingo Hartung, Jark Böttcher, Vineet Pande, and Volkhart Mj Li
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0301 basic medicine ,Open science ,Computer science ,QH301-705.5 ,Chemical probes ,Science ,General Biochemistry, Genetics and Molecular Biology ,Target validation ,03 medical and health sciences ,Science Forum ,Open Science ,Biochemistry and Chemical Biology ,Technology, Pharmaceutical ,Biology (General) ,Pharmaceutical industry ,Pharmacology ,Protein function ,General Immunology and Microbiology ,business.industry ,General Neuroscience ,Feature Article ,Proteins ,General Medicine ,Data science ,3. Good health ,030104 developmental biology ,Molecular Probes ,Medicine ,business - Abstract
Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (ext-link ext-link-type="uri" xlink:href="https://openscienceprobes.sgc-frankfurt.de"https://openscienceprobes.sgc-frankfurt.de/ext-linkext-link ext-link-type="uri" xlink:href="https://openscienceprobes.sgc-frankfurt.de/"//ext-link). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project.
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- 2018
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20. Designing Orally Bioavailable Peptide and Peptoid Macrocycles
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Alan M. Mathiowetz, Spiros Liras, and David Price
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0301 basic medicine ,chemistry.chemical_classification ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,010405 organic chemistry ,Peptoid ,Peptide ,Pharmacology ,01 natural sciences ,0104 chemical sciences ,Bioavailability - Published
- 2017
21. Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists
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Justin M. Mitchell, Joakim E. Swedberg, Spiros Liras, Roger B. Ruggeri, David A. Griffith, David J. Edmonds, David P. Fairlie, Paula M. Loria, David Price, David J. Craik, Christina I. Schroeder, Thomas Durek, and David R. Derksen
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Models, Molecular ,Agonist ,medicine.drug_class ,Peptidomimetic ,Peptide ,CHO Cells ,Glucagon-Like Peptide-1 Receptor ,Structure-Activity Relationship ,Cricetulus ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Conotoxin ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,Bicyclic molecule ,Chemistry ,Organic Chemistry ,Biological activity ,General Medicine ,Amino acid ,Biochemistry ,Peptidomimetics ,Conotoxins - Abstract
Type 2 diabetes mellitus (T2DM) results from compromised pancreatic β-cell function, reduced insulin production, and lowered insulin sensitivity in target organs resulting in hyperglycemia. The GLP-1 hormone has two biologically active forms, GLP-1-(7-37) and GLP-1-(7-36)amide, which are equipotent at the glucagon-like peptide-1 receptor (GLP-1R). These peptides are central both to normal glucose metabolism and dysregulation in T2DM. Several structurally modified GLP-1 analogues are now approved drugs, and a number of other analogues are in clinical trials. None of these compounds is orally bioavailable and all require parenteral delivery. Recently, a number of smaller peptidomimetics containing 11-12 natural and unnatural amino acids have been identified that have similar insulin regulating profiles as GLP-1. The α-conotoxins are a class of disulfide rich peptide venoms isolated from cone snails, and are known for their highly constrained structures and resistance to enzymatic degradation. In this study, we examined whether 11-residue peptidomimetics incorporated into α-conotoxin scaffolds, forming monocyclic or bicyclic compounds constrained by disulfide bonds and/or backbone cyclization, could activate the GLP-1 receptor (GLP-1R). Several compounds showed potent (nanomolar) agonist activity at GLP-1R, as evaluated via cAMP signaling. In addition, HPLC retention times and in silico calculations suggested that mono- and bicyclic compounds had more favorable n-octanol/water partition coefficients according to the virtual partition coefficient model (vLogP), while maintaining a smaller radius of gyration compared to corresponding uncyclized peptidomimetics. Our findings suggest that cyclic peptidomimetics provide a potential avenue for future design of potent, compact ligands targeting GLP-1R and possessing improved physicochemical properties.
- Published
- 2015
22. Peptide to Peptoid Substitutions Increase Cell Permeability in Cyclic Hexapeptides
- Author
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David Price, Melissa Thang, Heather Eng, Spiros Liras, Gilles H. Goetz, Joshua Schwochert, Chris Limberakis, R. Scott Lokey, Bhagyashree Khunte, Kelsie M. Rodriguez, Matthew P. Jacobson, Siegfried S. F. Leung, Alexandra R. Ponkey, Ray F. Berkeley, Michael J. Shapiro, Alan M. Mathiowetz, Rushia A. Turner, and Amit S. Kalgutkar
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Models, Molecular ,Magnetic Resonance Spectroscopy ,Membrane permeability ,Molecular Conformation ,Peptide ,Molecular Dynamics Simulation ,Biochemistry ,Permeability ,Cell Line ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Side chain ,Animals ,Structure–activity relationship ,Physical and Theoretical Chemistry ,chemistry.chemical_classification ,Chemistry ,Organic Chemistry ,Epithelial Cells ,Peptoid ,Nuclear magnetic resonance spectroscopy ,Combinatorial chemistry ,Cyclic peptide ,Permeability (electromagnetism) ,Biophysics ,Peptides - Abstract
The effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-methylated cyclic hexapeptide is examined. In general, substitutions maintained permeability but increased conformational heterogeneity. Diversification with nonproteinogenic side chains increased permeability up to 3-fold. Additionally, the conformational impact of peptoid substitutions within a β-turn are explored. Based on these results, the strategic incorporation of peptoid residues into cyclic peptides can maintain or improve cell permeability, while increasing access to diverse side-chain functionality.
- Published
- 2015
23. Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products
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Jarret W. Gardner, Cameron R. Pye, David Price, Katrina W. Lexa, Alan M. Mathiowetz, R. Scott Lokey, William M. Hewitt, Amit S. Kalgutkar, Spiros Liras, Matthew P. Jacobson, Kathryn C. R. Hund, Emerson Glassey, Andrew T. Bockus, and Joshua Schwochert
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Male ,Models, Molecular ,Cell Membrane Permeability ,Macrocyclic Compounds ,Magnetic Resonance Spectroscopy ,Chemical Phenomena ,Stereochemistry ,Administration, Oral ,Biological Availability ,Peptides, Cyclic ,Structure-Activity Relationship ,chemistry.chemical_compound ,Polyketide ,Amide ,Drug Discovery ,Animals ,Molecule ,Rats, Wistar ,chemistry.chemical_classification ,Biological Products ,Molecular Structure ,Hydrogen bond ,Chemistry ,Hydrogen Bonding ,Cyclic peptide ,Rats ,Solvent ,Membrane ,Microsomes, Liver ,Solvents ,Molecular Medicine ,Derivative (chemistry) - Abstract
Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation. Here we report the synthesis of cyclic hexapeptide diastereomers containing γ-amino acids (e.g., statines) and systematically investigate their structure-permeability relationships. These compounds were much more water-soluble and, in many cases, were both more membrane permeable and more stable to liver microsomes than a similar non-statine-containing derivative. Permeability correlated well with the extent of intramolecular hydrogen bonding observed in the solution structures determined in the low-dielectric solvent CDCl3, and one compound showed an oral bioavailability of 21% in rat. Thus, the incorporation of γ-amino acids offers a route to increase backbone diversity and improve ADME properties in cyclic peptide scaffolds.
- Published
- 2015
24. Short Hydrophobic Peptides with Cyclic Constraints Are Potent Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists
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Spiros Liras, David W. Piotrowski, David R. Derksen, W. Mei Kok, Timothy A. Hill, David Price, Kun Song, David P. Fairlie, Jacky Y. Suen, Paula M. Loria, David A. Griffith, Jane M. Withka, Alan M. Mathiowetz, David J. Edmonds, Vincent Mascitti, Huy N. Hoang, Chris Limberakis, Justin M. Mitchell, and Robert V. Stanton
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Models, Molecular ,Agonist ,Circular dichroism ,Stereochemistry ,medicine.drug_class ,CHO Cells ,Peptides, Cyclic ,Glucagon-Like Peptide-1 Receptor ,Protein Structure, Secondary ,Radioligand Assay ,Structure-Activity Relationship ,03 medical and health sciences ,Cricetulus ,0302 clinical medicine ,Protein structure ,Drug Discovery ,Cyclic AMP ,Receptors, Glucagon ,medicine ,Animals ,Humans ,Structure–activity relationship ,Receptor ,Nuclear Magnetic Resonance, Biomolecular ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Circular Dichroism ,biology.organism_classification ,Small molecule ,030220 oncology & carcinogenesis ,Molecular Medicine ,Hydrophobic and Hydrophilic Interactions ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonists at nM concentrations in a cAMP assay. 2D NMR and CD spectra revealed an N-terminal β-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small molecule agonists of the GLP-1 receptor to treat type 2 diabetes.
- Published
- 2015
25. Discovery of Potent and Orally Bioavailable Macrocyclic Peptide-Peptoid Hybrid CXCR7 Modulators
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Bhagyashree Khunte, Sangwoo Ryu, Jiangli Yan, Markus Boehm, Amit S. Kalgutkar, Kevin Beaumont, Janice A. Brown, Heather Eng, Laurie Tylaska, R. Scott Lokey, David Price, Elnaz Menhaji-Klotz, Chris Limberakis, Michael J. Shapiro, Guoyun Bai, Brian R. Holder, Liying Zhang, Sarah Lazzaro, Matthew P. Jacobson, Spiros Liras, David J. Earp, Alan M. Mathiowetz, Rhys M. Jones, Gilles H. Goetz, Siegfried S. F. Leung, Mahesh Ramaseshan, Rushia A. Turner, and Karen Atkinson
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0301 basic medicine ,Male ,Macrocyclic Compounds ,Stereochemistry ,Administration, Oral ,Biological Availability ,Madin Darby Canine Kidney Cells ,03 medical and health sciences ,Macrocyclic peptide ,chemistry.chemical_compound ,Chemokine receptor ,Peptoids ,Dogs ,Drug Discovery ,Potency ,Animals ,Humans ,Rats, Wistar ,Receptor ,chemistry.chemical_classification ,Receptors, CXCR ,Chemistry ,Peptoid ,Combinatorial chemistry ,Bioavailability ,Amino acid ,Rats ,Molecular Docking Simulation ,030104 developmental biology ,Molecular Medicine ,Selectivity ,Peptides - Abstract
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side-chain diversity well beyond that of natural amino acids. At the same time, theoretical calculations and experimental assays were used to track and reduce the polarity while closely monitoring the physicochemical properties. This strategy led to the discovery of macrocyclic peptide–peptoid hybrids with high CXCR7 binding affinities (Ki 5 × 10–6 cm/s). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.
- Published
- 2017
26. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain
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David W. Piotrowski, Jennifer A. Doudna, Kim F. McClure, Spiros Liras, Michael W. Bolt, Bruce A. Maguire, Austin Huang, Robert Dullea, Donna N. Petersen, Jun Xiao, Tim Rolph, Liuqing Wei, Jamie H. D. Cate, Allyn T. Londregan, Kieran F. Geoghegan, Nathanael G. Lintner, Paula M. Loria, and Khosla, Chaitan
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0301 basic medicine ,Proteomics ,Male ,Physiology ,Gene Expression ,Genetic Footprinting ,Biochemistry ,Medical and Health Sciences ,Mass Spectrometry ,0302 clinical medicine ,Heterocyclic Compounds ,Medicine and Health Sciences ,Ribosome profiling ,Molecular Targeted Therapy ,Biology (General) ,Spectrometric Identification of Proteins ,General Neuroscience ,Messenger RNA ,Stable Isotope Labeling by Amino Acids in Cell Culture ,Shine-Dalgarno sequence ,Biological Sciences ,Lipids ,3. Good health ,Cell biology ,Enzymes ,Body Fluids ,Nucleic acids ,Blood ,Cholesterol ,T arm ,Rabbits ,Cellular Structures and Organelles ,Anatomy ,Proprotein Convertase 9 ,General Agricultural and Biological Sciences ,Oxidoreductases ,Luciferase ,EF-Tu ,Research Article ,or More Rings ,QH301-705.5 ,Genetic Fingerprinting and Footprinting ,Biology ,Research and Analysis Methods ,General Biochemistry, Genetics and Molecular Biology ,Blood Plasma ,Cell Line ,03 medical and health sciences ,Prokaryotic translation ,Genetics ,Escherichia coli ,Initiation factor ,Animals ,Humans ,Molecular Biology Techniques ,Molecular Biology ,General Immunology and Microbiology ,Cell-Free System ,Agricultural and Veterinary Sciences ,Biology and Life Sciences ,Proteins ,Cell Biology ,4 or More Rings ,Proprotein convertase ,Rats ,Internal ribosome entry site ,030104 developmental biology ,Hela Cells ,Protein Biosynthesis ,Enzymology ,RNA ,Protein Translation ,Sprague-Dawley ,Ribosomes ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome that allows small molecules to specifically block translation of individual transcripts., Author summary Many disease-mediating proteins have proven difficult to target with traditional small-molecule pharmaceuticals. In this paper, we report that a small molecule, PF-06446846, directly inhibits translation of one such protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), by acting on the translating human ribosome. PF-06446846 causes the translating ribosome to stall soon after translating the PCSK9 signal sequence. We further show that PF-06446846 activity is dependent on the amino acid sequence of the nascent chain inside the ribosome exit tunnel. In a rat safety study, we observe decreases in plasma PCSK9, total cholesterol, and low-density lipoprotein (LDL) cholesterol. Using mass spectrometry in cell culture and ribosome profiling, we demonstrate that despite acting on the ribosome, which synthesizes every protein in the cell, PF-06446846 displays a high level of selectivity for PCSK9. This unexpected potential for small molecules to selectively inhibit the human ribosome opens the possibility for future development of small molecules targeting disease-mediating proteins that were previously thought to be undruggable.
- Published
- 2017
27. Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor
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Boris A. Chrunyk, Vincent Mascitti, Michael M. Baksh, Robert Dullea, Marc D. Roy, David Price, Cathy Préville, Carlos A. Sanhueza, Wen Lin, Elnaz Menhaji-Klotz, Meihua Tu, Amanda King-Ahmad, David F. Gebhard, Benjamin A. Thuma, Mark Ammirati, James E. Finley, Christopher T. Salatto, Spiros Liras, Sanjay Dutta, Shenping Liu, Benjamin Reidich, Kevin Beaumont, Ingrid A. Stock, Karen Atkinson, Rajesh Kumar, and M. G. Finn
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0301 basic medicine ,Models, Molecular ,Biodistribution ,Liver cytology ,Polymers ,Asialoglycoprotein Receptor ,010402 general chemistry ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,Catalysis ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Bridged Bicyclo Compounds ,Colloid and Surface Chemistry ,medicine ,Humans ,Drug Carriers ,Ligand efficiency ,Molecular Structure ,Chemistry ,Oxanorbornadiene ,General Chemistry ,Ketones ,Ligand (biochemistry) ,0104 chemical sciences ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,Hepatocyte ,Hepatocytes ,Asialoglycoprotein receptor ,Conjugate - Abstract
A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo. Assessment of the biodistribution in rodents of a prototypical Alexa647-labeled trivalent conjugate showed selective hepatocyte targeting with no detectable distribution in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed hepatocellular uptake and prolonged retention compared to a similar GalNAc derived trimer conjugate. Selective release in the liver of a passively permeable small-molecule cargo was achieved by retro-Diels-Alder cleavage of an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, the multicomponent construct described here represents a highly efficient delivery vehicle to hepatocytes.
- Published
- 2017
28. Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable
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Andrew J. Lucke, Huy N. Hoang, David J. Craik, David Price, Charles J. Rotter, Timothy A. Hill, David A. Griffith, David P. Fairlie, Daniel S. Nielsen, Spiros Liras, Roger B. Ruggeri, Rink-Jan Lohman, and David J. Edmonds
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Models, Molecular ,chemistry.chemical_classification ,Membrane permeability ,Protein Conformation ,Hydrogen bond ,Administration, Oral ,Biological Availability ,General Medicine ,General Chemistry ,Peptides, Cyclic ,Catalysis ,Cyclic peptide ,Bioavailability ,Solvent ,chemistry.chemical_compound ,chemistry ,Permeability (electromagnetism) ,Amide ,Side chain ,Organic chemistry ,Amino Acid Sequence ,Nuclear Magnetic Resonance, Biomolecular ,Oligopeptides - Abstract
The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR-derived structures, amide H-D exchange rates, and temperature-dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N-methylation.
- Published
- 2014
29. Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed
- Author
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Barbara Colless, Stephanie Chaousis, Timothy A. Hill, Martin J. Stoermer, Andrew J. Lucke, Rink-Jan Lohman, Ligong Liu, Daniel S. Nielsen, Spiros Liras, Roger B. Ruggeri, Charles J. Rotter, Conor C G Scully, David J. Edmonds, Huy N. Hoang, W. Mei Kok, David Price, David P. Fairlie, Paul V. Bernhardt, David A. Griffith, Christina I. Schroeder, and David J. Craik
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Drug ,chemistry.chemical_classification ,Hydrogen bond ,business.industry ,Stereochemistry ,media_common.quotation_subject ,Organic Chemistry ,Peptide ,Biochemistry ,Combinatorial chemistry ,Cyclic peptide ,3. Good health ,Bioavailability ,Amino acid ,chemistry.chemical_compound ,chemistry ,Amide ,Drug Discovery ,Lipinski's rule of five ,Medicine ,business ,media_common - Abstract
Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-methyl amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH protons, exhibit some degree of oral bioavailability (4-17%) approaching that of the heavily N-methylated drug cyclosporine (22%) under the same conditions. These simple cyclic peptides demonstrate that oral bioavailability is achievable for peptides that fall outside of rule-of-five guidelines without the need for N-methylation or modified amino acids.
- Published
- 2014
30. Fmoc-Based Synthesis of Disulfide-Rich Cyclic Peptides
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Spiros Liras, Christina I. Schroeder, Yen-Hua Huang, David Price, Olivier Cheneval, Phillip Walsh, David J. Craik, and Thomas Durek
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Cyclotides ,Peptide ,Peptides, Cyclic ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Solid-Phase Synthesis Techniques ,Peptide synthesis ,Amino Acid Sequence ,Cysteine ,Disulfides ,Peptide sequence ,Chromatography, High Pressure Liquid ,030304 developmental biology ,chemistry.chemical_classification ,Fluorenes ,0303 health sciences ,010405 organic chemistry ,Drug discovery ,Organic Chemistry ,Cystine knot ,Combinatorial chemistry ,Cyclic peptide ,0104 chemical sciences ,chemistry ,Cyclization ,Oxidation-Reduction - Abstract
Disulfide-rich cyclic peptides have exciting potential as leads or frameworks in drug discovery; however, their use is faced with some synthetic challenges, mainly associated with construction of the circular backbone and formation of the correct disulfides. Here we describe a simple and efficient Fmoc solid-phase peptide synthesis (SPPS)-based method for synthesizing disulfide-rich cyclic peptides. This approach involves SPPS on 2-chlorotrityl resin, cyclization of the partially protected peptide in solution, cleavage of the side-chain protecting groups, and oxidization of cysteines to yield the desired product. We illustrate this method with the synthesis of peptides from three different classes of cyclic cystine knot motif-containing cyclotides: Möbius (M), trypsin inhibitor (T), and bracelet (B). We show that the method is broadly applicable to peptide engineering, illustrated by the synthesis of two mutants and three grafted analogues of kalata B1. The method reduces the use of highly caustic and toxic reagents and is better suited for high-throughput synthesis than previously reported methods for producing disulfide-rich cyclic peptides, thus offering great potential to facilitate pharmaceutical optimization of these scaffolds.
- Published
- 2014
31. Comparative α-Helicity of Cyclic Pentapeptides in Water
- Author
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Praveer Gupta, Timothy A. Hill, David Price, Spiros Liras, David P. Fairlie, Frederik Diness, W. Mei Kok, Huy N. Hoang, Aline Dantas de Araujo, and Russell W. Driver
- Subjects
chemistry.chemical_classification ,Circular dichroism ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Circular Dichroism ,Temperature ,Water ,Thio ,Peptide ,General Chemistry ,Peptides, Cyclic ,Combinatorial chemistry ,Protein Structure, Secondary ,Catalysis ,Cyclic peptide ,chemistry.chemical_compound ,chemistry ,Helix ,Lactam ,Amino Acid Sequence ,Oligopeptides ,Linker ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
Helix-constrained polypeptides have attracted great interest for modulating protein-protein interactions (PPI). It is not known which are the most effective helix-inducing strategies for designing PPI agonists/antagonists. Cyclization linkers (X1-X5) were compared here, using circular dichroism and 2D NMR spectroscopy, for α-helix induction in simple model pentapeptides, Ac-cyclo(1,5)-[X1-Ala-Ala-Ala-X5]-NH2, in water. In this very stringent test of helix induction, a Lys1→Asp5 lactam linker conferred greatest α-helicity, hydrocarbon and triazole linkers induced a mix of α- and 3₁₀-helicity, while thio- and dithioether linkers produced less helicity. The lactam-linked cyclic pentapeptide was also the most effective α-helix nucleator attached to a 13-residue model peptide.
- Published
- 2014
32. Comparative α-Helicity of Cyclic Pentapeptides in Water
- Author
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Aline D. de Araujo, Huy N. Hoang, W. Mei Kok, Frederik Diness, Praveer Gupta, Timothy A. Hill, Russell W. Driver, David A. Price, Spiros Liras, and David P. Fairlie
- Subjects
General Medicine - Published
- 2014
33. Introduction
- Author
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Andrew S. Bell and Spiros Liras
- Published
- 2014
34. Small-molecule phosphodiesterase probes: discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1
- Author
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Artem G. Evdokimov, John M. Humphrey, Christopher W. am Ende, Brian Samas, Lorraine A. Lebel, Frank S. Menniti, Mahmoud N. Mansour, Eddie Yang, Eric P. Arnold, Stephen Jenkinson, Spiros Liras, Felix Vajdos, Jenna L. Head, Samuel P. Simons, and Jayvardhan Pandit
- Subjects
Pharmacology ,chemistry.chemical_classification ,Organic Chemistry ,Pharmaceutical Science ,Phosphodiesterase ,PDE1 ,Biology ,Blood–brain barrier ,Biochemistry ,Small molecule ,Calcium in biology ,Cyclic nucleotide ,chemistry.chemical_compound ,medicine.anatomical_structure ,Enzyme ,chemistry ,Drug Discovery ,medicine ,Quinazoline ,Molecular Medicine - Abstract
PDE1 is a family of calcium-activated, dual substrate phosphodiesterases expressed in both the CNS and periphery that play a role in the integration of intracellular calcium and cyclic nucleotide signaling cascades. Exploration of the potential in targeting this family of enzymes to treat neuropsychiatric disorders has been hampered by a lack of potent, selective, and brain penetrable PDE1 inhibitors. To identify such compounds we used high-throughput screening, structure-based design, and targeted synthetic chemistry to discover the 4-aminoquinazoline 7a (PF-04471141) and the 4-indanylquinazoline 27 (PF-04822163) each of which are PDE1 inhibitors that readily cross the blood brain barrier. These quinazoline-based PDE1-selective inhibitors represent valuable new tools to study the biological processes regulated by PDE1 and to begin to determine the potential therapeutic utility of such compounds to treat neuropsychiatric disorders.
- Published
- 2014
35. Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity
- Author
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Yun-Dong Wu, Spiros Liras, Kun Song, Mark Edward Flanagan, David Price, Tao Wang, Guoyun Bai, Fan Jiang, Zigang Li, Bingchuan Zhao, Huacan Lin, Yujie Wu, Meihua Tu, Mingsheng Xie, Adam M. Gilbert, Gilles H. Goetz, Alan A. Mathiowetz, Yuan Tian, and Qingzhou Zhang
- Subjects
chemistry.chemical_classification ,Models, Molecular ,Protein Conformation, alpha-Helical ,Circular dichroism ,Multidisciplinary ,010405 organic chemistry ,Stereochemistry ,Circular Dichroism ,Sulfoxide ,Peptide ,Nuclear magnetic resonance spectroscopy ,010402 general chemistry ,01 natural sciences ,Helicity ,Article ,0104 chemical sciences ,Ring size ,chemistry.chemical_compound ,chemistry ,Oxidation state ,Safrole ,Peptides ,Single crystal ,Oxidation-Reduction - Abstract
Inducing α-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide-containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce α-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone α-helicity.
- Published
- 2016
36. Macrocyclizations for Medicinal Chemistry: Synthesis of Druglike Macrocycles by High-Concentration Ullmann Coupling
- Author
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James C. Collins, David Price, Kathleen A. Farley, Spiros Liras, Keith James, and Chris Limberakis
- Subjects
High concentration ,Macrocyclic Compounds ,Chemistry, Pharmaceutical ,Aryl ,Organic Chemistry ,Imidazoles ,chemistry.chemical_element ,Chemistry Techniques, Synthetic ,Ring (chemistry) ,Copper ,Catalysis ,chemistry.chemical_compound ,Phenols ,chemistry ,Nucleophile ,Cyclization ,Drug Design ,Tyrosine ,Organic chemistry ,Phenol ,Imidazole ,Histidine - Abstract
Conditions have been identified for the efficient Ullmann macrocyclization of phenol and imidazole nucleophiles with aryl iodides at high reaction concentrations of up to 100 mM and using 5-10 mol % loading of an inexpensive copper catalyst. A range of substitution patterns and ring sizes are tolerated, and the method has been exemplified by the synthesis of a set of druglike macrocycles.
- Published
- 2012
37. A compound that directly and selectively stalls PCSK9 translation
- Author
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Jun Xiao, Tim Rolph, Spiros Liras, David W. Piotrowski, Nathanael G. Lintner, Austin Huang, Robert Dullea, Allyn T. Londregan, Paula M. Loria, Bruce A. Maguire, Jamie H. D. Cate, Kieran F. Geoghegan, Liuqing Wei, Michael W. Bolt, Jennifer A. Doudna, Kim F. McClure, and Donna N. Petersen
- Subjects
0303 health sciences ,PCSK9 ,Subtilisin ,Biology ,Proprotein convertase ,Ribosome ,3. Good health ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,Mechanism of action ,Biochemistry ,medicine ,Kexin ,Initiation factor ,Ribosome profiling ,medicine.symptom ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome, which allows small molecules to specifically block translation of individual transcripts.One Sentence SummaryA small-molecule PCSK9 inhibitor targets the human ribosome and selectively prevents PCSK9 synthesis.
- Published
- 2016
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38. Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro*
- Author
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David A. Griffith, David J. Edmonds, Spiros Liras, Roger B. Ruggeri, Christina I. Schroeder, Justin M. Mitchell, Joakim E. Swedberg, David J. Craik, David R. Derksen, David P. Fairlie, David Price, and Paula M. Loria
- Subjects
0301 basic medicine ,Agonist ,endocrine system ,medicine.drug_class ,Recombinant Fusion Proteins ,Peptide ,CHO Cells ,Peptide hormone ,Biochemistry ,Protein Structure, Secondary ,03 medical and health sciences ,Cricetulus ,Glucagon-Like Peptide 1 ,Cricetinae ,medicine ,Animals ,Humans ,Conotoxin ,Receptor ,Molecular Biology ,chemistry.chemical_classification ,030102 biochemistry & molecular biology ,biology ,Chemistry ,Venoms ,digestive, oral, and skin physiology ,Cell Biology ,biology.organism_classification ,Cyclic peptide ,3. Good health ,Cell biology ,030104 developmental biology ,Protein Structure and Folding ,cAMP-dependent pathway ,Exenatide ,Conotoxins ,Peptides ,hormones, hormone substitutes, and hormone antagonists - Abstract
Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with an extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP-1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide α-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fractional helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22-27) directing the binding of Phe(22) into a hydrophobic pocket on the GLP-1R.
- Published
- 2016
39. An Efficient Synthesis of Bridged Heterocycles from an Ir(I) Bis-Amination/Ring-Closing Metathesis Sequence
- Author
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Spiros Liras, Ryan A. Brawn, Kim F. McClure, and Cristiano Ruch Werneck Guimarães
- Subjects
Molecular Structure ,Chemistry ,Organic Chemistry ,chemistry.chemical_element ,Stereoisomerism ,Iridium ,Metathesis ,Biochemistry ,Catalysis ,Heterocyclic Compounds, Bridged-Ring ,Ring-closing metathesis ,Organic chemistry ,Molecule ,Amines ,Physical and Theoretical Chemistry ,Amination ,Acyclic diene metathesis - Abstract
The amination of bis-allylic imidates using an Iridium(I) catalyst leads to the efficient formation of 2,6-divinyl heterocycles. Careful screening of amines, solvents, and conditions has led to the discovery of a system that favors formation of the desired cis products with synthetically useful levels of diastereoselectivity, and these results are further explained by computer based transition state energy calculations. Exposure of the heterocycles to ring-closing metathesis catalysts leads to the desired bridged heterocyclic systems.
- Published
- 2012
40. Design and Discovery of 6-[(3S,4S)-4-Methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943), a Selective Brain Penetrant PDE9A Inhibitor for the Treatment of Cognitive Disorders
- Author
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Robin J. Kleiman, Christopher J. Schmidt, Michael L. Corman, Patrick Robert Verhoest, Christopher John Helal, Jamison B. Tuttle, Shenpinq Liu, Michelle Vanase-Frawley, Frank S. Menniti, Spiros Liras, Karen J. Coffman, Kari R. Fonseca, Michelle Marie Claffey, Caroline Proulx-Lafrance, Xinjun Hou, and Frederick R. Nelson
- Subjects
Genetically modified mouse ,Drug ,biology ,media_common.quotation_subject ,Pharmacology ,Chemical synthesis ,In vitro ,chemistry.chemical_compound ,chemistry ,Pyran ,Drug Discovery ,Amyloid precursor protein ,biology.protein ,Molecular Medicine ,Penetrant (biochemical) ,Selectivity ,media_common - Abstract
6-[(3S,4S)-4-Methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943) is a novel PDE9A inhibitor identified using parallel synthetic chemistry and structure-based drug design (SBDD) and has advanced into clinical trials. Selectivity for PDE9A over other PDE family members was achieved by targeting key residue differences between the PDE9A and PDE1C catalytic site. The physicochemical properties of the series were optimized to provide excellent in vitro and in vivo pharmacokinetics properties in multiple species including humans. It has been reported to elevate central cGMP levels in the brain and CSF of rodents. In addition, it exhibits procognitive activity in several rodent models and synaptic stabilization in an amyloid precursor protein (APP) transgenic mouse model. Recent disclosures from clinical trials confirm that it is well tolerated in humans and elevates cGMP in cerebral spinal fluid of healthy volunteers, confirmin...
- Published
- 2012
41. Exploring Aromatic Chemical Space with NEAT: Novel and Electronically Equivalent Aromatic Template
- Author
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Jeffrey A. Pfefferkorn, Alan M. Mathiowetz, Angel Guzman-Perez, Matthew Merrill Hayward, Brajesh K. Rai, John William Benbow, Cristiano Ruch Werneck Guimarães, Scot Richard Mente, Spiros Liras, Mary Theresa Didiuk, and Meihua Tu
- Subjects
Work (thermodynamics) ,Hydrogen bond ,Chemistry ,General Chemical Engineering ,Aryl ,Aromaticity ,General Chemistry ,Library and Information Sciences ,Hydrocarbons, Aromatic ,Piperazines ,Sildenafil Citrate ,Chemical space ,Computer Science Applications ,Characterization (materials science) ,chemistry.chemical_compound ,Dipole ,Transformation (function) ,Models, Chemical ,Purines ,Computational chemistry ,Drug Discovery ,Humans ,Quantum Theory ,Sulfones - Abstract
In this paper, we describe a lead transformation tool, NEAT (Novel and Electronically equivalent Aromatic Template), which can help identify novel aromatic rings that are estimated to have similar electrostatic potentials, dipoles, and hydrogen bonding capabilities to a query template; hence, they may offer similar bioactivity profiles. In this work, we built a comprehensive heteroaryl database, and precalculated high-level quantum mechanical (QM) properties, including electrostatic potential charges, hydrogen bonding ability, dipole moments, chemical reactivity, and othe properties. NEAT bioisosteric similarities are based on the electrostatic potential surface calculated by Brood, using the precalculated QM ESP charges and other QM properties. Compared with existing commercial lead transformation software, (1) NEAT is the only one that covers the comprehensive heteroaryl chemical space, and (2) NEAT offers a better characterization of novel aryl cores by using high-evel QM properties that are relevant to molecular interactions. NEAT provides unique value to medicinal chemists quickly exploring the largely uncharted aromatic chemical space, and one successful example of its application is discussed herein.
- Published
- 2012
42. Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains
- Author
-
Laurence Philippe, David Price, James C. Collins, Falco-Magnus Meyer, James Bradow, Brendan Borin, Alan M. Mathiowetz, Chris Limberakis, Kun Song, Keith James, and Spiros Liras
- Subjects
chemistry.chemical_classification ,Molecular Structure ,biology ,Stereochemistry ,Phenylalanine ,Aryl ,Aryl halide ,Organic Chemistry ,Stereoisomerism ,Peptide ,biology.organism_classification ,Peptides, Cyclic ,Amino acid ,Peptide Conformation ,Solutions ,chemistry.chemical_compound ,chemistry ,Side chain ,Tyrosine ,Tetra ,Amino Acids ,Peptides - Abstract
A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization of suitably functionalized tri-, tetra- and pentapeptides via Suzuki-Miyaura cross-coupling has been used to generate side chain to side chain, biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges possessing three different configurations, meta-meta, meta-ortho, and ortho-meta, were systematically explored through regiochemical variation of the aryl halide and aryl boronate coupling partners, allowing fine-tuning of the resultant macrocycle conformation. Suzuki-Miyaura macrocyclizations were successfully achieved both in solution and on solid phase for all three sizes of peptide. This approach constitutes a means of constraining peptide conformation via direct carbogenic fusion of side chains of naturally occurring amino acids such as phenylalanine and tyrosine, and so is complementary to strategies involving non-natural, for example, hydrocarbon, bridges.
- Published
- 2012
43. Discovery of (S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus
- Author
-
Jing Chen, Spiros Liras, Manthena V.S. Varma, Judith L. Treadway, Martha L. Minich, Laurel Sweet, John D. Knafels, Karen Atkinson, Nahor Haddish-Berhane, Angel Guzman-Perez, Benjamin D. Stevens, Alan Robertson, Sharad B. Murdande, David B. Duignan, Mark Ammirati, Timothy P. Rolph, William J. Zavadoski, Christopher S. Jones, Patricia Bourassa, Jeffrey A. Pfefferkorn, John Litchfield, Lili Yao, Kevin J. Filipski, Margit MacDougall, Levenia Baker, John C. Pettersen, Theresa D’Aquila, Ayman El-Kattan, Bo Feng, Francis Bourbonais, Meihua Tu, Robert J. Aiello, Gary Erik Aspnes, Jianwei Bian, David R. Derksen, Paul DaSilva-Jardine, Beijing Tan, James A. Landro, Over Cabrera, Rachel E. Kosa, Hud Lawrence Risley, Shenping Liu, Amanda L. Lapworth, and Nicole Barucci
- Subjects
Blood Glucose ,Male ,Models, Molecular ,medicine.medical_specialty ,Allosteric regulation ,Enzyme Activators ,Organic Anion Transporters ,In Vitro Techniques ,Hypoglycemia ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,Dogs ,Insulin-Secreting Cells ,Internal medicine ,Glucokinase ,Drug Discovery ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Glucose homeostasis ,Tissue Distribution ,Rats, Wistar ,chemistry.chemical_classification ,Chemistry ,Activator (genetics) ,Imidazoles ,Nicotinic Acids ,Type 2 Diabetes Mellitus ,Stereoisomerism ,Haplorhini ,medicine.disease ,Small molecule ,Rats ,Enzyme ,Endocrinology ,Diabetes Mellitus, Type 2 ,Hepatocytes ,Molecular Medicine ,Allosteric Site ,Protein Binding - Abstract
Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.
- Published
- 2012
44. Optimizing PK properties of cyclic peptides: the effect of side chain substitutions on permeability and clearance
- Author
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Bhagyashree Khunte, David Price, Charles J. Rotter, Heather Eng, Siegfried S. F. Leung, Yizhong Zhang, Manthena V.S. Varma, Chris Limberakis, Spiros Liras, R. Scott Lokey, Amit S. Kalgutkar, Raman Sharma, Matthew P. Jacobson, Alan M. Mathiowetz, Kathleen A. Farley, and Arthur C Rand
- Subjects
Pharmacology ,chemistry.chemical_classification ,Chemotype ,Organic Chemistry ,In vitro toxicology ,Pharmaceutical Science ,Peptide ,Bioinformatics ,Biochemistry ,Article ,Cyclic peptide ,Bioavailability ,chemistry ,Permeability (electromagnetism) ,Drug Discovery ,Side chain ,Biophysics ,Molecular Medicine ,Amino acid residue - Abstract
A series of cyclic peptides were designed and prepared to investigate the physicochemical properties that affect oral bioavailabilty of this chemotype in rats. In particular, the ionization state of the peptide was examined by the incorporation of naturally occurring amino acid residues that are charged in differing regions of the gut. In addition, data was generated in a variety of in vitro assays and the usefulness of this data in predicting the subsequent oral bioavailability observed in the rat is discussed.
- Published
- 2012
45. On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds
- Author
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Spiros Liras, Cayla M. McEwen, Rushia A. Turner, David Price, Taha Rezai, Amit S. Kalgutkar, Roger G. Linington, Alan M. Mathiowetz, R. Scott Lokey, Matthew P. Jacobson, Arthur C Rand, Yizhong Zhang, Vladimir Gelev, Chad M. Renzelman, Siegfried S. F. Leung, Tina R White, and Jonathan N. Bauman
- Subjects
Male ,Membrane permeability ,Stereochemistry ,Chemistry, Pharmaceutical ,Biological Availability ,Peptide ,010402 general chemistry ,Methylation ,Peptides, Cyclic ,01 natural sciences ,Article ,Structure-Activity Relationship ,Drug Discovery ,Animals ,Combinatorial Chemistry Techniques ,Structure–activity relationship ,Computer Simulation ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,Molecular mass ,010405 organic chemistry ,Drug discovery ,Cell Biology ,Combinatorial chemistry ,Cyclic peptide ,Rats ,0104 chemical sciences ,Bioavailability ,chemistry ,Selectivity - Abstract
Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat.
- Published
- 2011
46. Use of Structure-Based Design to Discover a Potent, Selective, In Vivo Active Phosphodiesterase 10A Inhibitor Lead Series for the Treatment of Schizophrenia
- Author
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Carol B. Fox, Spiros Liras, Douglas S. Chapin, Frederick R. Nelson, Jayvardhan Pandit, Xinjun Hou, Christopher John Helal, John M. Humphrey, Christopher J. Schmidt, Thomas Allen Chappie, Kimberly F. Fennell, Frank S. Menniti, Zhijun Kang, Julia Cianfrogna, Judith A. Siuciak, Mary C. MacDougall, Kari R. Fonseca, Rebecca E. O’Connor, Lois K. Chenard, Eric S. Marr, Lorraine A. Lebel, Laura McDowell, and Robert D. Williams
- Subjects
Models, Molecular ,Databases, Factual ,Phosphodiesterase Inhibitors ,Protein Conformation ,In Vitro Techniques ,Crystallography, X-Ray ,Cocrystal ,Permeability ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Avoidance Learning ,Animals ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Binding site ,Cyclic GMP ,ADME ,Mice, Knockout ,Binding Sites ,Phosphoric Diester Hydrolases ,Chemistry ,Rational design ,Phosphodiesterase ,Corpus Striatum ,Biochemistry ,Blood-Brain Barrier ,Drug Design ,Microsomes, Liver ,Schizophrenia ,Molecular Medicine ,Structure based ,PDE10A ,Antipsychotic Agents - Abstract
Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.
- Published
- 2011
47. Identification of a Brain Penetrant PDE9A Inhibitor Utilizing Prospective Design and Chemical Enablement as a Rapid Lead Optimization Strategy
- Author
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Christopher J. Schmidt, Frank S. Menniti, Kari R. Fonseca, Spiros Liras, Robert D. Williams, Michelle Vanase-Frawley, Frederick R. Nelson, Christopher John Helal, Eric S. Marr, Patrick Robert Verhoest, Xinjun Hou, Shenping Liu, Lois K. Chenard, Michael L. Corman, Anne W. Schmidt, Caroline Proulx-Lafrance, and Robin J. Kleiman
- Subjects
Models, Molecular ,Phosphodiesterase Inhibitors ,Phosphoric Diester Hydrolases ,Brain ,Hydrogen Bonding ,Computational biology ,Mice ,chemistry.chemical_compound ,chemistry ,Biochemistry ,3',5'-Cyclic-AMP Phosphodiesterases ,In vivo ,Drug Discovery ,Animals ,Humans ,Molecular Medicine ,Penetrant (biochemical) ,Cyclic GMP - Abstract
By use of chemical enablement and prospective design, a novel series of selective, brain penetrant PDE9A inhibitors have been identified that are capable of producing in vivo elevations of brain cGMP.
- Published
- 2009
48. Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the Treatment of Schizophrenia†Coordinates of the PDE10A crystal structures have been deposited in the Protein Data Bank for compound 1 (3HQW), 2 (3HQY), 3 (3HQW) and 9 (3HR1)
- Author
-
John F. Harms, Christopher J. Schmidt, Anne W. Schmidt, Caroline Proulx-Lafrance, Eric S. Marr, Michael L. Corman, Kari R. Fonseca, Frank S. Menniti, Douglas S. Chapin, Rebecca E. O’Connor, Jayvardhan Pandit, Xinjun Hou, Judith A. Suiciak, Spiros Liras, Frederick R. Nelson, and Patrick Robert Verhoest
- Subjects
Male ,Models, Molecular ,PF-2545920 ,Molecular model ,Stereochemistry ,In Vitro Techniques ,Crystallography, X-Ray ,Chemical synthesis ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Drug Discovery ,Avoidance Learning ,Animals ,Humans ,Structure–activity relationship ,Mice, Knockout ,Binding Sites ,Molecular Structure ,biology ,Phosphoric Diester Hydrolases ,Chemistry ,Quinoline ,Brain ,Phosphodiesterase ,Hydrogen Bonding ,Rats ,Macaca fascicularis ,Enzyme inhibitor ,Microsomes, Liver ,Quinolines ,Schizophrenia ,biology.protein ,Pyrazoles ,Molecular Medicine ,Female ,PDE10A ,Antipsychotic Agents ,Protein Binding - Abstract
By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.
- Published
- 2009
49. Phosphodiesterases and Their Inhibitors
- Author
-
Spiros Liras, Andrew S. Bell, Spiros Liras, and Andrew S. Bell
- Subjects
- Phosphodiesterases--Inhibitors--Therapeutic use, Cyclic nucleotide phosphodiesterases, Phosphodiesterases--Inhibitors
- Abstract
Written by the pioneers of Viagra, the first blockbuster PDE inhibitor drug. Beginning with a review of the first wave of phosphodiesterase (PDE) inhibitors, this book focuses on new and emerging PDE targets and their inhibitors. Drug development options for all major human PDE families are discussed and cover diverse therapeutic fields, such as neurological/psychiatric, cardiovascular/metabolic, pain, and allergy/respiratory diseases. Finally, emerging chemotherapeutic applications of PDE inhibitors against malaria and other tropical diseases are discussed.
- Published
- 2014
50. Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability
- Author
-
Barbara Colless, David Price, David J. Craik, Susan E. Northfield, Conan K. Wang, Stephanie Chaousis, Joakim E. Swedberg, and Spiros Liras
- Subjects
Pharmacology ,chemistry.chemical_classification ,Quantitative structure–activity relationship ,Chemistry ,Organic Chemistry ,Quantitative Structure-Activity Relationship ,Biological membrane ,Peptide ,General Medicine ,Nuclear magnetic resonance spectroscopy ,Molecular Dynamics Simulation ,Combinatorial chemistry ,Models, Biological ,Peptides, Cyclic ,Cyclic peptide ,Peptide Conformation ,Molecular dynamics ,Drug Discovery ,Lipophilicity ,Humans ,Caco-2 Cells - Abstract
An increasing number of macrocyclic peptides that cross biological membranes are being reported, suggesting that it might be possible to develop peptides into orally bioavailable therapeutics; however, current understanding of what makes macrocyclic peptides cell permeable is still limited. Here, we synthesized 62 cyclic hexapeptides and characterized their permeability using in vitro assays commonly used to predict in vivo absorption rates, i.e. the Caco-2 and PAMPA assays. We correlated permeability with experimentally measured parameters of peptide conformation obtained using rapid methods based on chromatography and nuclear magnetic resonance spectroscopy. Based on these correlations, we propose a model describing the interplay between peptide permeability, lipophilicity and hydrogen bonding potential. Specifically, peptides with very high permeability have high lipophilicity and few solvent hydrogen bond interactions, whereas peptides with very low permeability have low lipophilicity or many solvent interactions. Our model is supported by molecular dynamics simulations of the cyclic peptides calculated in explicit solvent, providing a structural basis for the observed correlations. This prospective exploration into biomarkers of peptide permeability has the potential to unlock wider opportunities for development of peptides into drugs.
- Published
- 2015
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