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Drug Discovery Efforts (drug + discovery_effort)
Selected AbstractsA personal account of the role of peptide research in drug discovery: the case of hepatitis C,JOURNAL OF PEPTIDE SCIENCE, Issue 1 2001Antonello Pessi Abstract Although peptides themselves are not usually the end products of a drug discovery effort, peptide research often plays a key role in many aspects of this process. This will be illustrated by reviewing the experience of peptide research carried out at IRBM in the course of our study of hepatitis C virus (HCV). The target of our work is the NS3/4A protease, which is essential for maturation of the viral polyprotein. After a thorough examination of its substrate specificity we fine-tuned several substrate-derived peptides for enzymology studies, high-throughput screening and as fluorescent probes for secondary binding assays. In the course of these studies we made the key observation: that the protease is inhibited by its own cleavage products. Single analog and combinatorial optimization then derived potent peptide inhibitors. The crucial role of the NS4A cofactor was also addressed. NS4A is a small transmembrane protein, whose central domain is the minimal region sufficient for enzyme activation. Structural studies were performed with a peptide corresponding to the minimal activation domain, with a series of product inhibitors and with both. We found that NS3/4A is an induced fit enzyme, requiring both the cofactor and the substrate to acquire its bioactive conformation; this explained some puzzling results of ,serine-trap' type inhibitors. A more complete study on NS3 activation, however, requires the availability of the full-length NS4A protein. This was prepared by native chemical ligation, after sequence engineering to enhance its solubility; structural studies are in progress. Current work is focused on the P, region of the substrate, which, at variance with the P region, is not used for ground state binding to the enzyme and might give rise to inhibitors showing novel interactions with the enzyme. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd. [source] The Use of Biochemical and Biophysical Tools for Triage of High-Throughput Screening Hits , A Case Study with Escherichia coli Phosphopantetheine AdenylyltransferaseCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2010J. Richard Miller High-throughput screening is utilized by pharmaceutical researchers and, increasingly, academic investigators to identify agents that act upon enzymes, receptors, and cellular processes. Screening hits include molecules that specifically bind the target and a greater number of non-specific compounds. It is necessary to ,triage' these hits to identify the subset worthy of further exploration. As part of our antibacterial drug discovery effort, we applied a suite of biochemical and biophysical tools to accelerate the triage process. We describe application of these tools to a series of 9-oxo-4,9-dihydropyrazolo[5,1-b]quinazoline-2-carboxylic acids (PQ) hits from a screen of Escherichia coli phosphopantetheine adenylyltransferase (PPAT). Initial confirmation of specific binding to phosphopantetheine adenylyltransferase was obtained using biochemical and biophysical tools, including a novel orthogonal assay, isothermal titration calorimetry, and saturation transfer difference NMR. To identify the phosphopantetheine adenylyltransferase sub-site bound by these inhibitors, two techniques were utilized: steady-state enzyme kinetics and a novel 19F NMR method in which fluorine-containing fragments that bind the ATP and/or phosphopantetheine sites serve as competitive reporter probes. These data are consistent with PQs binding the ATP sub-site. In addition to identification of a series of PPAT inhibitors, the described hit triage process is broadly applicable to other enzyme targets in which milligram quantities of purified target protein are available. [source] Viral proteinases: targets of opportunityDRUG DEVELOPMENT RESEARCH, Issue 6 2006Chelsea M. Byrd Abstract During antiviral drug development, any essential stage of the viral life cycle can serve as a potential drug target. Since most viruses encode specific proteases whose cleavage activity is required for viral replication, and whose structure and activity are unique to the virus and not the host cell, these enzymes make excellent targets for drug development. Success using this approach has been demonstrated with the plethora of protease inhibitors approved for use against HIV. This discussion is designed to review the field of antiviral drug development, focusing on the search for protease inhibitors, while highlighting some of the challenges encountered along the way. Protease inhibitor drug discovery efforts highlighting progress made with HIV, HCV, HRV, and vaccinia virus as a model system are included. Drug Dev. Res. 67:501,510, 2006. © 2006 Wiley-Liss, Inc. [source] The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism , or inverse agonism , as potential obesity treatment and other therapeutic useJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2007S. Xie Pharm D student Summary There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB1 (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity. [source] TRP channels as therapeutic targets: hot property, or time to cool down?NEUROGASTROENTEROLOGY & MOTILITY, Issue 8 2006G. A. Hicks Abstract,Transient receptor potential (TRP) channels are involved in a wide range of processes ranging from osmoregulation, thermal, chemical and sensory signalling, and potentially in the pathophysiology associated with several diseases. Patents for TRPV1 antagonists alone span diseases ranging across chronic pain, neuropathies, headache, bladder disorders, irritable bowel syndrome (IBS), gastro-oesophageal reflux disease (GORD), and cough amongst others. Most research is currently focused around those TRP channels involved in sensory processes, with the neurogastroenterology and motility field playing a major role, for example, through recent discoveries of differential roles for TRPV receptor subtypes in chemosensitivity and mechanosensitivity of visceral afferents. At this time, however, the understanding of the role of even TRPV1, let alone most of the other TRP channels in disease pathophysiology is only just beginning, and although enthusiasm around the therapeutic potential for modulators of these channels is understandable, based largely upon the experience of the effects of natural ligands, such as capsaicin, the sheer size and complexity of the TRP family as a whole must serve as a warning against expecting too much too soon from drug discovery efforts. [source] N -Linked Glycosylated , -Peptides Are Resistant to Degradation by Glycoamidase ACHEMISTRY & BIODIVERSITY, Issue 12 2005Matthew , -Peptides are resistant to degradation by a variety of proteolytic enzymes that rapidly degrade natural , -peptides. This is one of many characteristics that make , -peptides an attractive class of compounds for drug discovery efforts. To further understand the molecular recognition properties of , -peptides and the ability of enzymes to degrade them, we have synthesized a series of N- linked glycosylated , - and , -peptides, and tested their stability towards a glycosidase. We found that glyco- , -peptides that contain N- acetylglucosamine (1) or N,N -diacetylchitobiose (2) are completely stable to degradation by glycoamidase A. In comparison, the glyco- , -peptides 3 and 4 containing N -acetylglucosamine or N,N -diacetylchitobiose are degraded. Inhibition experiments using increasing concentrations of a glyco- , -peptide fail to inhibit degradation of the corresponding glyco- , -peptide, even when the glyco- , -peptide is at a 128-fold higher concentration than the glyco- , -peptide. Evidently, the glyco- , -peptides have a much weaker affinity for the active site of the glycosidase than the corresponding glyco- , -peptide. These and the results with proteolytic enzymes suggest that the additional CH2 group introduced into the , -amino acid residues causes , -peptides not to be recognized by hydrolytic enzymes. The results described herein suggest the potential of , -peptides that are functionalized with carbohydrates for biological and biomedical investigations, without having to be concerned about the carbohydrate being removed. [source] Small-Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer TherapeuticsCHEMMEDCHEM, Issue 4 2010Stefan Peukert Dr. Abstract Inhibitors of the Hedgehog (Hh) molecular signaling pathway have emerged in recent years as a promising new class of potential therapeutics for cancer treatment. Numerous drug discovery efforts have resulted in the identification of a wide variety of small molecules that target different members of this pathway, including Smoothened (Smo), Sonic hedgehog protein (Shh), and Gli1. Several Smo inhibitors have now entered human clinical trials, and successful proof-of-concept studies have been carried out in patients with defined genetic mutations in the Hh pathway. This review provides a general overview of three main topics in this rapidly expanding area: 1),the various types of biological assays and in,vivo models that have been employed for the identification and optimization of Hh pathway inhibitors; 2),Smo inhibitors reported to date, including recent clinical results where available; and 3),efforts toward the identification and characterization of inhibitors of other members of the Hh pathway. [source] | |||||||||||||