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

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 C3 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.

The use of hydroxypropylamine containing glycopeptide compounds as potential protease inhibitors is described for the first time. Docking results are in agreement with the experimental HIV-PR activity.Figure optionsDownload as PowerPoint slideHighlights
► First example of a hydroxypropylamine transition state analog for protease inhibition.
► Facile synthesis to new class of carbapeptides.
► Good correlation between IC50 and modelling.