Peptidic modulators of protein‐protein interactions: Progress and challenges in computational design

Abstract

With the decline in productivity of drug‐development efforts, novel approaches to rational drug design are being introduced and developed. Naturally occurring and synthetic peptides are emerging as novel promising compounds that can specifically and efficiently modulate signaling pathways in vitro and in vivo. We describe sequence‐based approaches that use peptides to mimic proteins in order to inhibit the interaction of the mimicked protein with its partners. We then discuss a structure‐based approach, in which protein‐peptide complex structures are used to rationally design and optimize peptidic inhibitors. We survey flexible peptide docking techniques and discuss current challenges and future directions in the rational design of peptidic inhibitors. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 505–513, 2009.This article was originally published online as an accepted preprint. The “Published Online”date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Computational Studies on Structural, Excitation, and Charge-Transfer Properties of Ureidopeptidomimetics

“…11 UPs have also been found to act as HIV-1 protease inhibitors 12,13 and are betterknown as antibiotics. 4 UPs have been synthesized with various substituents, ranging from organic (carboxylic groups, amines, etc.) 14,15 to inorganic (ferrocene units) 16 functional groups.…”

Polypeptide Modulators of Caspase Recruitment Domain (CARD)-CARD-mediated Protein-Protein Interactions

“…Therefore, the still unexplored design and evaluation of polypeptides defined as short protein domains and synthetic peptides targeting CARD-CARD interactions could provide a first level of ground information in this direction. We have therefore adopted an integrated strategy to define polypeptide modulators of a representative CARD-CARD-mediated protein interaction by first producing individual CARDs in bacteria; second, devising a rational approach based on the design of peptide mimics of the interacting proteins (25); and third, using phage display technology (26). In particular, we initially paid attention to the Apaf-1/PC9 interaction and to the different in vitro formats described to analyze this interaction.…”

Stereoselective synthesis and structure determination of a bicyclo[3.3.2]decapeptide

“…3,4 Branched peptide chains are expected to be conformationally constrained or even completely rigid, resulting in stronger and more selective target binding and increased resistance to proteolytic degradation compared to linear peptides. The use of standard amino acid building blocks furthermore ensures relatively low toxicity and unproblematic metabolism, which is one key advantage of peptides when considering therapeutic use.…”