Enhancing alpha-helicity HIV peptide increases affinity for human monoclonal antibody 2F5.(Brief Article)

2003 FEB 5 - (NewsRx.com & NewsRx.net) -- "The synthetic peptide DP178, derived from the carboxyl-terminal heptad repeat region of human immunodeficiency virus type 1 GP41 protein is a potent inhibitor of viral-mediated fusion and contains the sequence ELDKWA, which constitutes the recognition epitope for the broadly neutralizing human monoclonal antibody 2F5. Efforts at eliciting a 2F5-like immune response by immunization with peptides or fusion proteins containing this sequence have not met with success, possibly because of incorrect structural presentation of the epitope. Although the structure of the carboxyl-terminal heptad repeat on the virion is not known, several recent reports have suggested a propensity for a-helical conformation," researchers in the United States report.

"We have examined DP178 in the context of a model for optimized alpha-helices and show that the native sequence conforms poorly to the model," said Joseph G. Joyce and colleagues at the Merck Research Laboratories in West Point, Pennsylvania. "Solution conformation of DP178 was studied by circular dichroism and NMR spectroscopy and found to be predominantly random, consistent with previous reports. NMR mapping was used to show that the low percentage of a-helix present was localized to residues Glu(662) through Asn(671), a region encompassing the 2F5 epitope.

"Using NH2-terminal extensions derived from either GP41 or the yeast GCN4 leucine zipper dimerization domain, we designed peptide analogs in which the average helicity is significantly increased compared with DP178 and show that these peptides exhibit both a modest increase in affinity for 2F5 using a novel competitive solution-based binding assay and an increased ability to inhibit viral entry in a single-cycle infectivity model."

The researchers continued, "Selected peptides were conjugated to carrier protein and used for guinea ...