Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex.

Bioorg Med Chem 2017 10 9;25(19):5114-5127. Epub 2017 Apr 9.

Department of Hematology, Kumamoto University of Medicine, Kumamoto 860-8556, Japan; Department of Infectious Diseases, Kumamoto University of Medicine, Kumamoto 860-8556, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD 20892, USA; Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, Shinjuku, Tokyo 162-8655, Japan.

Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme K of 0.025nM and antiviral IC of 69nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27Å resolution. These structures revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site.

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https://linkinghub.elsevier.com/retrieve/pii/S09680896173073
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http://dx.doi.org/10.1016/j.bmc.2017.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617771PMC
October 2017
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