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.

Graphical abstractThe 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 full-size imageDownload 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.