1izh

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spinqualitylabelsall models 1izh, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Inhibitor of HIV protease with unusual binding mode potently inhibiting multi-resistant protease mutants

Overview

Protease inhibitors (PIs) are an important class of drugs for the, treatment of HIV infection. However, in the course of treatment, resistant, viral variants with reduced sensitivity to PIs often emerge and become a, major obstacle to successful control of viral load. On the basis of a, compound equipotently inhibiting HIV-1 and 2 proteases (PR), we have, designed a pseudopeptide inhibitor, QF34, that efficiently inhibits a wide, variety of PR variants. In order to analyze the potency of the inhibitor, we constructed PR species harboring the typical (signature) mutations that, confer resistance to commercially available PIs. Kinetic analyses showed, that these mutated PRs were inhibited up to 1,000-fold less efficiently by, the clinically approved PIs. In contrast, all PR species were effectively, inhibited by QF34. In a clinical study, we have monitored 30 HIV-positive, patients in the Czech Republic undergoing highly active antiretroviral, therapy, and have identified highly PI resistant variants. Kinetic, analyses revealed that QF34 retained its subnanomolar potency against, multi-drug resistant PR variants. X-ray crystallographic analysis and, molecular modeling experiments explained the wide specificity of QF34:, this inhibitor binds to the PR in an unusual manner, thus avoiding contact, sites that are mutated upon resistance development, and the unusual, binding mode and consequently the binding energy is therefore preserved in, the complex with a resistant variant. These results suggest a promising, route for the design of second-generation PIs that are active against a, variety of resistant PR variants.

About this Structure

1IZH is a Single protein structure of sequence from Human immunodeficiency virus 1 with Q50 as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

Reference

Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains., Weber J, Mesters JR, Lepsik M, Prejdova J, Svec M, Sponarova J, Mlcochova P, Skalicka K, Strisovsky K, Uhlikova T, Soucek M, Machala L, Stankova M, Vondrasek J, Klimkait T, Kraeusslich HG, Hilgenfeld R, Konvalinka J, J Mol Biol. 2002 Dec 6;324(4):739-54. PMID:12460574

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