Rational development of beta-peptide inhibitors of human cytomegalovirus entry.
Human cytomegalovirus (HCMV) is a pervasive and significant pathogen. At present, there is no HCMV vaccine, and the available drugs target only replication events. Thus, new therapeutic strategies are needed. HCMV fusion appears to require interactions of alpha-helical regions in viral surface glycoproteins gB and gH. Oligomers of beta-amino acids ("beta-peptides") are attractive unnatural scaffolds for mimicry of specific protein surfaces, because beta-peptides adopt predictable helical conformations and resist proteolysis. Here, we report the development of beta-peptides designed to mimic the gB heptad repeat and block HCMV entry. The most potent beta-peptide inhibits HCMV infection in a cell based-assay with an IC50 of approximately 30 microm. Consistent with our structure-based design strategy, inhibition is highly specific for HCMV relative to other related viruses. Mechanistic studies indicate that inhibitory beta-peptides act by disrupting membrane fusion. Our findings raise the possibility that beta-peptides may provide a general platform for development of a new class of antiviral agents and that inhibitory beta-peptides will constitute new tools for elucidating viral entry mechanisms.
English
Emily Payne
EP
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
Chumanov
Robert S
RS
Gellman
Samuel H
SH
Compton
Teresa
T
D016475:3T3 Cells; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D015195:Drug Design; D005347:Fibroblasts; D006801:Humans; D020128:Inhibitory Concentration 50; D008561:Membrane Fusion / Q000187:drug effects; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins / Q000737:chemistry
D000998:Antiviral Agents; D010455:Peptides; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; C071440:glycoprotein H, Cytomegalovirus