期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 22, 页码 5072-5077出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.10.023
关键词
Coronavirus; 3CLpro; Feline infectious peritonitis; Structure-based drug design; Peptidomimetics
资金
- National Institutes of Health via the National Institute of Allergy and Infectious Diseases [AI085089, AI26603]
- Purdue University
- Walther Cancer Foundation
- NIH Grant [P30 CA023168]
- U.S. DOE [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- Purdue Center for Cancer Research Macromolecular Crystallography
Feline infectious peritonitis (FIP) is a deadly disease that effects both domestic and wild cats and is caused by a mutation in feline coronavirus (FCoV) that allows the virus to replicate in macrophages. Currently, there are no treatments or vaccines available for the treatment of FIP even though it kills approximately 5% of cats in multi-cat households per year. In an effort to develop small molecule drugs targeting FIP for the treatment of cats, we screened a small set of designed peptidomimetic inhibitors for inhibition of FIPV-3CL(pro), identifying two compounds with low to sub-micromolar inhibition, compound 6 (IC50 = 0.59 +/- 0.06 mu M) and compound 7 (IC50 = 1.3 +/- 0.1 mu M). We determined the first X-ray crystal structure of FIPV-3CL(pro) in complex with the best inhibitor identified, compound 6, to a resolution of 2.10 angstrom to better understand the structural basis for inhibitor specificity. Our study provides important insights into the structural requirements for the inhibition of FIPV-3CL(pro) by peptidomimetic inhibitors and expands the current structural knowledge of coronaviral 3CL(pro) architecture. (C) 2015 Elsevier Ltd. All rights reserved.
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