Design, synthesis, and evaluation of in vivo potency and selectivity of epoxysuccinyl-based inhibitors of papain-family cysteine proteases Journal Article
| Authors: | Sadaghiani, A. M.; Verhelst, S. H. L.; Gocheva, V.; Hill, K.; Majerova, E.; Stinson, S.; Joyce, J. A.; Bogyo, M. |
| Article Title: | Design, synthesis, and evaluation of in vivo potency and selectivity of epoxysuccinyl-based inhibitors of papain-family cysteine proteases |
| Abstract: | The papain-family cathepsins are cysteine proteases that are emerging as promising therapeutic targets for a number of human disease conditions ranging from osteoporosis to cancer. Relatively few selective inhibitors for this family exist, and the in vivo selectivity of most existing compounds is unclear. We present here the synthesis of focused libraries of epoxysuccinyl-based inhibitors and their screening in crude tissue extracts. We identified a number of potent inhibitors that display selectivity for endogenous cathepsin targets both in vitro and in vivo. Importantly, the selectivity patterns observed in crude extracts were generally retained in vivo, as assessed by active-site labeling of tissues from treated animals. Overall, this study identifies several important compound classes and highlights the use of activity-based probes to assess pharmacodynamic properties of small-molecule inhibitors in vivo. © 2007 Elsevier Ltd. All rights reserved. |
| Keywords: | mass spectrometry; mouse; animal; animals; mice; drug screening; drug evaluation, preclinical; cysteine proteinase inhibitors; drug design; proteomics; animalia; drug antagonism; rat; rats; cysteine proteinase inhibitor; high performance liquid chromatography; chromatography, high pressure liquid; synthesis; peptide library; intubation, gastrointestinal; indicators and reagents; epoxy compounds; epoxide; intraperitoneal drug administration; injections, intraperitoneal; chembiol; dyes, reagents, indicators, markers and buffers; papain; digestive tract intubation |
| Journal Title: | Chemistry and Biology |
| Volume: | 14 |
| Issue: | 5 |
| ISSN: | 1074-5521 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2007-05-01 |
| Start Page: | 499 |
| End Page: | 511 |
| Language: | English |
| DOI: | 10.1016/j.chembiol.2007.03.010 |
| PUBMED: | 17524981 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 28" - "Export Date: 17 November 2011" - "CODEN: CBOLE" - "Source: Scopus" |
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