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

Authors :: Kneller DW
Agniswamy J
Ghosh AK
Weber IT
Source :: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2019 Oct 29; Vol. 519 (1), pp. 61-66. Date of Electronic Publication: 2019 Aug 29.
Publication Year :: 2019
Abstract: Drug-resistance threatens effective treatment of HIV/AIDS. Clinical inhibitors, including darunavir (1), are ineffective for highly resistant protease mutant PR20, however, 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.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)

Subjects :: Antiviral Agents chemistry
Crystallography, X-Ray
HIV Protease Inhibitors chemistry
Humans
Kinetics
Models, Molecular
Molecular Conformation
Mutation
Antiviral Agents pharmacology
Drug Resistance, Viral drug effects
HIV Protease metabolism
HIV Protease Inhibitors pharmacology
HIV-1 drug effects

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