Small molecule inhibitors of hantavirus infection

Abstract

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.

Human pathogenic hantaviruses and prevention of infection

“…However, the therapeutic potential of these compounds needs to be further refined by the optimization of solubility along with the pharmacokinetics, as well as in vivo studies using animal models. 97 In the case that efficient and well-tolerated drugs can consisting of N protein and glycoproteins after expression in Chinese hamster ovary cells and self-aggregation. 85 In mice, these VLPs induced specific humoral and cellular immune responses.…”

Hantavirus infection: a global zoonotic challenge

“…The hantavirus genome consists of three segments, designated L (large), M (middle), and S (small). The L segment encodes an RNA-dependent RNA polymerase; the M segment encodes a glycoprotein precursor that is further processed to produce Gn and Gc transmembrane glycoproteins; and the S segment encodes a nucleocapsid protein (Hall et al, 2010). Despite the differences in distribution between Old World and New World hantaviruses in various geographic areas and the various diseases they induce, they exhibit a similar organization of nucleotide sequences and similar aspects in their life cycles (Jonsson et al, 2010).…”

Hantaviruses—Infections, Epidemiology and Hosts

“…Treatment with ribavirin early in the course of infection can lower the mortality in severe courses of HFRS, but has no effect in treatment of HCPS (Huggins et al 1986;Chapman et al 1999;Mertz et al 2004). Novel therapeutic strategies targeting specific steps of the viral replication cycle are under investigation and comprise small molecular inhibitors of the viral entry receptor integrin β3 that may block the entry of pathogenic Old and New World viruses (Larson et al 2005;Hall et al 2010). …”