Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20

Journal Article · Thu Aug 29 00:00:00 EDT 2019 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2019.08.126· OSTI ID:1572565

Kneller, Daniel W. ^[1]; Agniswamy, Johnson ^[1]; Ghosh, Arun K. ^[2]; Weber, Irene T.  ^[1]

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1. Georgia State Univ., Atlanta, GA (United States)
2. Purdue Univ., West Lafayette, IN (United States)

Drug-resistance threatens effective treatment of HIV/AIDS. Clinical inhibitors, including darunavir (1), are ineffective for highly resistant protease mutant PR20, however, here antiviral compound 2 derived from 1 with fused tricyclic group at P2, extended amino-benzothiazole P2’ ligand and two fluorine atoms on P1 shows 16-fold better inhibition of PR20 enzyme activity. Crystal structures of PR20 and wild-type PR complexes reveal how the extra groups of 2 counteract the expanded ligand-binding pocket, dynamic flaps, and faster dimer dissociation of PR20.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
• Grant/Contract Number: W-31-109-Eng-38; AI150461; AI150466
• OSTI ID: 1572565
• Alternate ID(s): OSTI ID: 1703108
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 519, Issue 1; ISSN 0006-291X
• Publisher: Elsevier
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

60 APPLIED LIFE SCIENCES
drug resistance
HIV protease
antiretroviral inhibitor
structure-based design
x-ray crystallography