New approaches for dissecting protease functions to improve probe development and drug discovery.
Proteases are well-established targets for pharmaceutical development because of their known enzymatic mechanism and their regulatory roles in many pathologies. However, many potent clinical lead compounds have been unsuccessful either because of a lack of specificity or because of our limited understanding of the biological roles of the targeted protease. In order to successfully develop protease inhibitors as drugs, it is necessary to understand protease functions and to expand the platform of inhibitor development beyond active site-directed design and in vitro optimization. Several newly developed technologies will enhance assessment of drug selectivity in living cells and animal models, allowing researchers to focus on compounds with high specificity and minimal side effects in vivo. In this review, we highlight advances in the development of chemical probes, proteomic methods and screening tools that we feel will help facilitate this paradigm shift in drug discovery.
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Edgar
E
Deu
Martijn
M
Verdoes
Matthew
M
Bogyo
D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D040901:Proteomics / Q000379:methods
D011480:Protease Inhibitors; D010447:Peptide Hydrolases