Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 566, Issue -, Pages 30-35Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.05.094
Keywords
Drug resistance; HIV protease; Protease inhibitor; X-ray crystallography
Categories
Funding
- National Institute of Health [AI150461, AI150466]
- Georgia State University Molecular Basis of Disease fellowship
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The emergence of multidrug resistant HIV strains has severely reduced the effectiveness of antiretroviral therapy, making antiviral inhibitors targeting MDR proteases valuable as therapeutic agents. Substituted inhibitors derived from clinical inhibitor darunavir show significantly improved inhibition of drug resistant variants, providing potential for new treatment options.
The emergence of multidrug resistant (MDR) HIV strains severely reduces the effectiveness of antiretroviral therapy. Clinical inhibitor darunavir (1) has picomolar binding affinity for HIV-1 protease (PR), however, drug resistant variants like PRS17 show poor inhibition by 1, despite the presence of only two mutated residues in the inhibitor-binding site. Antiviral inhibitors that target MDR proteases like PRS17 would be valuable as therapeutic agents. Inhibitors 2 and 3 derived from 1 through substitutions at P1, P2 and P2. positions exhibit 3.4- to 500-fold better inhibition than clinical inhibitors for PRS17 with the exception of amprenavir. Crystal structures of PRS17/2 and PRS17/3 reveal how these inhibitors target the two active site mutations of PRS17. The substituted methoxy P2 group of 2 forms new interactions with G48V mutation, while the modified bis-fluoro-benzyl P1 group of 3 forms a halogen interaction with V82S mutation, contributing to improved inhibition of PRS17. (C) 2021 Elsevier Inc. All rights reserved.
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