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

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.

SUBMITTER: Kneller DW

PROVIDER: S-EPMC7251940 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Kneller Daniel W DW Agniswamy Johnson J Ghosh Arun K AK Weber Irene T IT

Biochemical and biophysical research communications 20190829 1

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 pocke ...[more]

PMID: 31474336

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