Ligand modifications to reduce the relative resistance of multi-drug resistant HIV-1 protease

Tamaria G. Dewdney, Yong Wang, Zhigang Liu, Shiv K. Sharma, Samuel J. Reiter, Joseph S. Brunzelle, Iulia A. Kovari, Patrick M. Woster, Ladislau C. Kovari*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Proper proteolytic processing of the HIV-1 Gag/Pol polyprotein is required for HIV infection and viral replication. This feature has made HIV-1 protease an attractive target for antiretroviral drug design for the treatment of HIV-1 infected patients. To examine the role of the P1 and P1′positions of the substrate in inhibitory efficacy of multi-drug resistant HIV-1 protease 769 (MDR 769), we performed a series of structure-function studies. Using the original CA/p2 cleavage site sequence, we generated heptapeptides containing one reduced peptide bond with an L to F and A to F double mutation at P1 and P1′ (F-r-F), and an A to F at P1′ (L-r-F) resulting in P1/P1′ modified ligands. Here, we present an analysis of co-crystal structures of CA/p2 F-r-F, and CA/p2 L-r-F in complex with MDR 769. To examine conformational changes in the complex structure, molecular dynamic (MD) simulations were performed with MDR769-ligand complexes. MD trajectories show the isobutyl group of both the lopinavir analog and the CA/p2 L-r-F substrate cause a conformational change of in the active site of MDR 769. IC50 measurements suggest the non identical P1/P1′ ligands (CA/p2 L-r-F and lopinavir analog) are more effective against MDR proteases as opposed to identical P1/P1′ligands. Our results suggest that a non identical P1/P1′composition may be more favorable for the inhibition of MDR 769 as they induce conformational changes in the active site of the enzyme resulting in disruption of the two-fold symmetry of the protease, thus, stabilizing the inhibitor in the active site.

Original languageEnglish (US)
Pages (from-to)7430-7434
Number of pages5
JournalBioorganic and Medicinal Chemistry
Issue number23
StatePublished - Dec 1 2013


  • Crystallography
  • Drug design
  • Drug resistance
  • HIV-1 protease
  • Lopinavir

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmaceutical Science
  • Organic Chemistry


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