Hydrophobic interactions and the design of receptor mimetic peptides.

Abstract

The possibility that hydrophobic interactions may be used as a basis for the design of receptor mimetic peptides for small peptide hormones that lack the potential to adopt amphiphilic secondary structures was tested by designing and characterizing receptor mimetic peptides for gamma-endorphin. The receptor mimetic peptides were designed to exhibit a pattern of hydrophobic surfaces in an antiparallel orientation matching that of the peptide hormone in an extended conformation. An ELISA-based assay was used to determine the relative binding affinities of receptor mimetic peptides, control peptides and antisense peptides to gamma-endorphin immobilized on a surface. The inhibition constant for the best gamma-endorphin receptor mimetic peptide was 1.6 microM. No binding was detected for scrambled control peptides or the antisense-derived peptide mimetic to the limit of their respective solubilities. Sera from rabbits immunized with a gamma-endorphin receptor mimetic peptide were used to immunopurify the ligand-binding domain of the human opiate receptor and were cross-reactive with purified bovine opiate receptor. These results suggest that patterns of hydrophobicity can provide a rational basis for designing receptor mimetic peptides and may provide an explanation for the ability of some antisense peptides to bind to their cognate hormones and to elicit antibodies cross-reactive with hormone receptors.