Rational development of β-peptide inhibitors of human cytomegalovirus entry

Abstract

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 α-helical regions in viral surface glycoproteins gB and gH. Oligomers of β-amino acids ("β- peptides") are attractive unnatural scaffolds for mimicry of specific protein surfaces, because β-peptides adopt predictable helical conformations and resist proteolysis. Here, we report the development of β-peptides designed to mimic the gB heptad repeat and block HCMV entry. The most potent β-peptide inhibits HCMV infection in a cell based-assay with an IC50 of ∼30 μM. Consistent with our structure-based design strategy, inhibition is highly specific for HCMV relative to other related viruses. Mechanistic studies indicate that inhibitory β-peptides act by disrupting membrane fusion. Our findings raise the possibility that β-peptides may provide a general platform for development of a new class of antiviral agents and that inhibitory β-peptides will constitute new tools for elucidating viral entry mechanisms. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.