Library Construction, Selection and Modification Strategies to Generate Therapeutic Peptide-Based Modulators of Protein–Protein Interactions

Abstract

In the modern age of proteomics, vast numbers of protein-protein interactions (PPIs) are being identified as causative agents in pathogenesis, and are thus attractive therapeutic targets for intervention. Although traditionally regarded unfavorably as druggable agents relative to small molecules, peptides in recent years have gained considerable attention. Their previous dismissal had been largely due to the susceptibility of unmodified peptides to the barriers and pressures exerted by the circulation, immune system, proteases, membranes and other stresses. However, recent advances in high-throughput peptide isolation techniques, as well as a huge variety of direct modification options and approaches to allow targeted delivery, mean that peptides and their mimetics can now be designed to circumvent many of these traditional barriers. As a result, an increasing number of peptide-based drugs are reaching clinical trials and patients beyond.

Designing helical peptide inhibitors of protein–protein interactions

“…[7] Particularly for longer peptides, an element of rational design can help focus the search on sequences likely to enhance function. In some design problems it is important to consider binding specificity and to improve the affinity of a peptide for one target but not for paralogous family members; this is a consideration in many of the case studies described below.…”

A New Magnetic Resonance Imaging Probe Specifically Targeting Vascular Endothelial Growth Factor Receptor 2:Synthesis, Characterization and Biological Evaluation

“…Generally, the imaging component of probes includes iron-or Gd-based contrast agents, while the targeting ligands popularly studied are antibodies, peptides and aptamers. Peptides are particularly advantageous because of their low molecular weight, ease of transportation and storage, great stability and ease of modification 17,18 . For example, recent studies have demonstrated that the use of  v  3 integrin, aminopeptidase N, and angiopoietin could provide targeting of a tumour and its vascular endothelial cells 19,20 .…”

An Approach to Derive Functional Peptide Inhibitors of Transcription Factor Activity

“…Many rational design approaches, library screens, and selection systems exist and have resulted in the successful identification of molecules capable of binding to given TF targets, but a key challenge remains in ensuring that target binding will translate into ablation of function. 17 , 19 Selection using a well-studied target exemplar in this work was required to provide suitable antagonists that validate the assay concept. Various methodologies have produced peptide-based cJun antagonists that target the broad LZ binding interface.…”