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

• Published in: Biochemical and biophysical research communications Vol. 519; no. 1; pp. 61 - 66
• Main Authors: Kneller, Daniel W., Agniswamy, Johnson, Ghosh, Arun K., Weber, Irene T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.10.2019; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Antiretroviral inhibitor; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Crystallography, X-Ray; Drug resistance; Drug Resistance, Viral - drug effects; HIV protease; HIV Protease - metabolism; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; Humans; Kinetics; Models, Molecular; Molecular Conformation; Mutation; Structure-based design; X-ray crystallography; X-ray crystallography; PR; 2; THF; HIV; Antiretroviral inhibitor; Structure-based design; AIDS; 1, DRV; Drug resistance; HIV protease; Ki
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.08.126

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. •Clinical inhibitors of HIV-1 protease are ineffective against drug-resistant mutant PR20.•PR20 is an excellent model for evaluating new inhibitors for drug-resistant HIV protease.•New antiviral compound derived from darunavir scaffold has better inhibition of PR20.•Two fluorine atoms of inhibitor introduce new halogen bonds and stabilize PR20.