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

Abstract

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.

Towards rational computational peptide design

“…In both scenarios a functional motif will allow these peptides to target and inhibit or enhance interactions and pathways. Peptides have some intrinsic limitations like fast degradation and difficulty crossing barriers that might make them precursors of other molecules such as modified peptides (Szabó et al, 2022), mini-proteins (Cao et al, 2022) and small molecule peptidomimetics (Rubin et al, 2018;Perez, 2021). However, predicting the initial structure and identifying high affinity binders will be critical to develop these peptide derivatives.…”

Effects of solvents on the conformational profile of Balaram's peptide: a computational study

“…12 Following the discussion outlined in previous paragraphs, we considered interesting to unravel the role played by the solvents in inducing changes in the peptide ensemble of conformations through computational studies. [20][21][22] Therefore, the present work describes the results of a series of molecular dynamics simulations of the octapeptide (Balaram's peptide) in diverse explicit solvents including chloroform, DMSO, MeOH and water to discuss the role played by the solvents, determined by their specific features. Specifically, the conformational profile of Balaram's peptide in diverse solvents was assessed by means of 10 ms molecular dynamics (MD) simulations at 300 K. Simulations were carried out on a model peptide consisting of the octapeptide capped with an acetyl group at the N-terminus and a methylamide at the C-terminus, as shown in Fig.…”