Small molecule inhibitors of hantavirus infection

Hantaviruses use αvβ3 integrins on the surface of human host cells as a gateway to invasion, hence compounds that target this receptor may be used as antiviral agents. To accomplish this aim, new peptidomimetic compounds were selected based on similarity to a cyclic peptide known to bind the αvβ3 receptor. This first round of biological screening identified peptidomimetic molecules which were effective hantavirus inhibitors in the low micromolar range, two thousand times more potent than the original cyclic peptide. Pharmacophore models were built to broaden the structural diversity of the second set of compounds screened. Structure–activity relationships (SAR) were drawn from the entire dataset. Further characterization by dose–response studies revealed that three compounds had potency in the nanomolar range. Selectivity assays with a panel of hantaviruses supported the mechanism of inhibition by targeting the αvβ3 receptor, through the β3 integrin.

New entry inhibitors of hantaviruses that selectively target β3 integrin, utilized by Andes and Sin Nombre virus, were selected using LBVS and cell-based assays. These bioactive compounds are thought to bind the receptor at host cell plasma membrane, thus preventing viral entry at the cell surface.Figure optionsDownload as PowerPoint slide