Exploiting Knowledge on Structure-Activity Relationships for Designing Peptidomimetics of Endogenous Peptides

Endogenous peptides are important mediators in cell communication, being consequently involved in many physiological processes. Their use as therapeutic agents is limited due to their poor pharmacokinetic profile. To circumvent this drawback, alternative diverse molecules based on the stereochemical features that confer their activity can be synthesized, using them as guidance; from peptide surrogates provided with a better pharmacokinetic profile, to small molecule peptidomimetics, through cyclic peptides. The design process requires a competent use of the structure-activity results available on individual peptides. Specifically, it requires synthesis and analysis of the activity of diverse analogs, biophysical information and computational work. In the present work, we show a general framework of the process and show its application to two specific examples: the design of selective AT1 antagonists of angiotensin and the design of selective B2 antagonists of bradykinin.