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Synthetic, structural mimetics of the ?-hairpin flap of HIV-1 protease inhibit enzyme function.

ABSTRACT: Small-molecule mimetics of the ?-hairpin flap of HIV-1 protease (HIV-1 PR) were designed based on a 1,4-benzodiazepine scaffold as a strategy to interfere with the flap-flap protein-protein interaction, which functions as a gated mechanism to control access to the active site. Michaelis-Menten kinetics suggested our small-molecules are competitive inhibitors, which indicates the mode of inhibition is through binding the active site or sterically blocking access to the active site and preventing flap closure, as designed. More generally, a new bioactive scaffold for HIV-1PR inhibition has been discovered, with the most potent compound inhibiting the protease with a modest K(i) of 11 ?M.

SUBMITTER: Chauhan J

PROVIDER: S-EPMC4661106 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function.

Chauhan Jay J Chen Shen-En SE Fenstermacher Katherine J KJ Naser-Tavakolian Aurash A Reingewertz Tali T Salmo Rosene R Lee Christian C Williams Emori E Raje Mithun M Sundberg Eric E DeStefano Jeffrey J JJ Freire Ernesto E Fletcher Steven S

Bioorganic & medicinal chemistry 20150907 21

Small-molecule mimetics of the β-hairpin flap of HIV-1 protease (HIV-1 PR) were designed based on a 1,4-benzodiazepine scaffold as a strategy to interfere with the flap-flap protein-protein interaction, which functions as a gated mechanism to control access to the active site. Michaelis-Menten kinetics suggested our small-molecules are competitive inhibitors, which indicates the mode of inhibition is through binding the active site or sterically blocking access to the active site and preventing ...[more]

PMID: 26474665

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