Insights into the mechanism of drug resistance: X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex

Zhigang Liu, Ravikiran S. Yedidi, Yong Wang, Tamaria G. Dewdney, Samuel J. Reiter, Joseph S. Brunzelle, Iulia A. Kovari, Ladislau C. Kovari*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Ritonavir (RTV) is a first generation HIV-1 protease inhibitor with rapidly emerging drug resistance. Mutations at residues 46, 54, 82 and 84 render the HIV-1 protease drug resistant against RTV. We report the crystal structure of multi-drug resistant (MDR) 769 HIV-1 protease (carrying resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84 and 90) complexed with RTV and the in vitro enzymatic IC50 of RTV against MDR HIV-1 protease. The structural and functional studies demonstrate significant drug resistance of MDR HIV-1 protease against RTV, arising from reduced hydrogen bonds and Van der Waals interactions between RTV and MDR HIV-1 protease.

Original languageEnglish (US)
Pages (from-to)232-238
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume431
Issue number2
DOIs
StatePublished - Feb 8 2013

Keywords

  • HIV-1 protease
  • IC50
  • Multi-drug resistance
  • Ritonavir
  • X-ray crystallography

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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