7MYP

Crystal Structure of HIV-1 PRS17 with GRL-44-10A

Summary for 7MYP

• Entry DOI: 10.2210/pdb7myp/pdb
• Descriptor: Protease, GLYCEROL, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: hiv-1 protease, multi drug resistant, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22433.08

Authors

Agniswamy, J.,Weber, I.T. (deposition date: 2021-05-21, release date: 2021-07-28, Last modification date: 2023-10-18)

Primary citation

Agniswamy, J.,Kneller, D.W.,Ghosh, A.K.,Weber, I.T.
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 .
Biochem.Biophys.Res.Commun., 566:30-35, 2021

PubMed Abstract: 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 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 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 with the exception of amprenavir. Crystal structures of PR/2 and PR/3 reveal how these inhibitors target the two active site mutations of PR. 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.

PubMed: 34111669
DOI: 10.1016/j.bbrc.2021.05.094

Experimental method

X-RAY DIFFRACTION (1.65 Å)