Small molecule inhibitors of hantavirus infection.
Hantaviruses use α(v)β(3) 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 α(v)β(3) 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 α(v)β(3) receptor, through the β(3) integrin.
Hall
Pamela R
PR
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Leitão
Andrei
A
Ye
Chunyan
C
Kilpatrick
Kathleen
K
Hjelle
Brian
B
Oprea
Tudor I
TI
Larson
Richard S
RS
D004305:Dose-Response Relationship, Drug; D006476:Orthohantavirus / Q000187:drug effects; D018778:Hantavirus Infections / Q000517:prevention & control*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D039661:Integrin beta3; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D010456:Peptides, Cyclic