Peptide inhibition of human cytomegalovirus infection

Melnik, Lilia I; Garry, Robert F; Morris, Cindy A

The WWIHS is a computational approach, based upon an experimentally determined algorithm to estimate the propensity of an amino acid sequence to interact with lipid membrane interfaces [49] . Using this method, we identified several regions of HCMV gB with high interfacial hydrophobicity. Peptides that are analogous to several of these regions inhibited HCMV infectivity at low μM concentrations (Figure 3 , 4, 5, 6, 7 and 8). When tested in combination certain combinations of peptides (peptides 264-291 and 297-315) displayed increased inhibition of infectivity at concentrations of 125 nM (Figure 8) . These results suggest that the HCMV inhibitory peptides identified here may serve as Figure 2 Determination of regions within gB that display a high propensity to interact with the lipid surface of cell membranes by using Wimley-White Interfacial Hydrophobicity Scale (WWIHS). WWIHS identifies segments of proteins that prefer a transbilayer helix conformation to an unfolded interfacial location. We used the Interface Scale of the Membrane Protein explorer (MpeX version 3.0) computer program to identify these particular segments of HCMV gB. The Interface scale measures a residue's free energy of transfer within an unfolded polypeptide chain from water to a phosphocholine bilayer. We identified nine segments of HCMV gB that display high propensity to interact with the lipid surface of cell membrane, and designed peptides, ranging from 19 to 31 amino acids in length, that are analogous to the identified regions of gB. the basis for potential antiviral therapies. The success of the inhibition of fusion greatly depends, not only on biophysical properties of synthesized peptides and their concentrations, but also on the size and shape of the binding pocket of HCMV gB. It is possible that the potency of the peptides, either alone or in combination, can be increased by modifying the sequence of the peptides or by conjugating the peptide(s) to other molecules.