Synthesis and molecular modelling studies of novel carbapeptide analogs for inhibition of HIV-1 protease

Eur J Med Chem. 2012 Jul:53:13-21. doi: 10.1016/j.ejmech.2012.03.027. Epub 2012 Apr 4.

Abstract

Novel glycopeptides containing amino acids such as valine and alanine were designed, synthesized and tested for inhibition of the wild type C-SA HIV-1 protease enzyme. The incorporation of dipeptide sequences Val-Ala/Ala-Val to the sugar B-amino acid at two side chain positions resulted in a series of nine novel compounds. Compounds 3a, 3b, 3c, 3d, 4a, 4b and 5 displayed significant activities against the HIV protease enzyme. The glycopeptides are orders of magnitude less toxic to human MT-4 cells than lopinavir. Computational results were in good agreement with the experimental HIV-PR activity. The sugar hydroxyl group at the C(3) position interacts with the enzymatic Asp25/Asp25' residues. The docked position of the inhibitor is preserved during MD simulations and at least five hydrogen bond forms between the inhibitor and the enzymatic pocket. The results provide a platform for the progress of more effective carbohydrate supported inhibitors of HIV-1 and other aspartic proteases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chemistry Techniques, Synthetic
  • Esters
  • Glycopeptides / chemical synthesis*
  • Glycopeptides / metabolism
  • Glycopeptides / pharmacology*
  • Glycopeptides / toxicity
  • HIV Protease / chemistry
  • HIV Protease / metabolism*
  • HIV-1 / enzymology*
  • Humans
  • Models, Molecular*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / toxicity
  • Protein Conformation

Substances

  • Esters
  • Glycopeptides
  • Protease Inhibitors
  • HIV Protease