Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains

Jan Weber, Jeroen R. Mesters, Martin Lepšík, Jana Prejdová, Martin Švec, Jana Šponarová, Petra Mlčochová, Kristina Skalická, Kvido Stříšovský, Táňa Uhlíková, Milan Souček, Ladislav Machala, Marie Staňková, Jiří Vondrášek, Thomas Klimkait, Hans Georg Kraeusslich, Rolf Hilgenfeld, Jan Konvalinka*

*Corresponding author for this work
47 Citations (Scopus)


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 1000-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.

Original languageEnglish
JournalJournal of Molecular Biology
Issue number4
Pages (from-to)739-754
Number of pages16
Publication statusPublished - 01.01.2002

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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