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Publication Abstract from PubMed

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 PR(S17) 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 PR(S17) 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 PR(S17) with the exception of amprenavir. Crystal structures of PR(S17)/2 and PR(S17)/3 reveal how these inhibitors target the two active site mutations of PR(S17). 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 PR(S17).

Novel HIV PR inhibitors with C4-substituted bis-THF and bis-fluoro-benzyl target the two active site mutations of highly drug resistant mutant PR(S17).,Agniswamy J, Kneller DW, Ghosh AK, Weber IT Biochem Biophys Res Commun. 2021 Aug 20;566:30-35. doi:, 10.1016/j.bbrc.2021.05.094. Epub 2021 Jun 7. PMID:34111669^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.