Tailoring Peptidomimetics for Targeting Protein–Protein Interactions

Abstract

Protein-protein interactions (PPI) are a hallmark of cellular signaling.

Role of the Axonal Initial Segment in Psychiatric Disorders: Function, Dysfunction, and Intervention

“…Although nascent, it has the potential to tremendously expand the repertoire of targets available for the pharmaceutical industry (142, 143). Through the engineering of small molecules or peptidomimetics (144, 145) that interact with and disrupt specific protein–protein interfaces, the effects of the inhibitor on the signaling network of the cell would be restricted from n edges ( n  = number of potential PPI between the targeted protein and the entire proteome) to a single edge. This would vastly increase the potential specificity without diminishing effectiveness.…”

“…This would vastly increase the potential specificity without diminishing effectiveness. In addition, selective targeting of protein surfaces prevents global disruption of protein expression levels, which may upregulate alternative and compensatory pathways that reverse treatment effects and replace critical “disease-promoting” factors, leading to relapse (144). In the context of dysregulation at the AIS, this targeted multi-protein approach has the potential to restore function as a consequence of a specific deficiency while having a minimal impact on other properly functioning pathways.…”

“…Alternative approaches could include the study of allosteric PPI modulators, compounds that bind at a site distant from the interaction interface that induce conformation changes which alter the PPI, as well as fragment-based approaches that involve searching two separate compounds joined by a linker to better probe chemical space (148, 149). However, the difficulty of translating biochemical assays to actual human therapies manifests as concerns in stability, pharmacokinetics/bioavailability, and toxicity, and poses a substantial barrier toward effective therapies that target the PPI (144). …”

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“…The Wnt pathway has Tcf-Lef target proteins which cause intestinal adenocarcinomas, myeloid leukemia and prostate cancer. Peptidomimetics are capable of β-Catenin/Tcf Lef complex disruption, decreased Tcf-Lef mediated gene activation 41 .…”

Les chimiothèques ciblant les interactions protéine-protéine

“…Un effort général a donc été entrepris en milieu académique, dans l'industrie pharmaceutique et chez les fournisseurs de molécules, afin de développer des collections de molécules appartenant à d'autres régions de l'espace chimique et dédiées à ce type de cibles. Les premiers efforts pour développer des molécules capables de perturber les interactions protéine-protéine reposaient sur la conception de mimes d'éléments de structures secondaires présents à l'interface, tels que les hélices , les brins , les coudes ou les poly-prolines [32][33][34]. Ces peptidomimétiques constituent une excellente source de composés pour la construction de chimiothèques focalisées.…”