Designing peptidomimetic antagonists for peptide receptors: topochemical differences of agonists and antagonists

Conclusions

Based on the results from these studies it is clear that the development of de novo approaches to peptidomimetic antagonist design presents very substantial challenges. Those features of structure and dynamic behavior that are critical to receptor binding and transduction must be carefully distinguished from those that are necessary only for specific binding/molecular recognition in both the ligand and the receptor. Thus, not only will true peptidomimetic antagonists require appropriate template structures that can mimic constrained peptide backbone conformations, but careful consideration of topographical constraint of side chain groups in the ligand also will be essential. We are now translating these findings into the design and synthesis of non-peptide peptidomimetic antagonist analogues.