Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer

Abstract

New chemical inhibitors of protein–protein interactions are needed to propel advances in molecular pharmacology. Peptoids are peptidomimetic oligomers with the capability to inhibit protein-protein interactions by mimicking protein secondary structure motifs. Here we report the in silico design of a macrocycle primarily composed of peptoid subunits that targets the β-catenin:TCF interaction. The β-catenin:TCF interaction plays a critical role in the Wnt signaling pathway which is over-activated in multiple cancers, including prostate cancer. Using the Rosetta suite of protein design algorithms, we evaluate how different macrocycle structures can bind a pocket on β-catenin that associates with TCF. The in silico designed macrocycles are screened in vitro using luciferase reporters to identify promising compounds. The most active macrocycle inhibits both Wnt and AR-signaling in prostate cancer cell lines, and markedly diminishes their proliferation. In vivo potential is demonstrated through a zebrafish model, in which Wnt signaling is potently inhibited.

Peptoids with Substituents on the Backbone Carbons as Conformationally Constrained Synthetic Oligoamides

“…Kirshenbaum and coworkers conducted detailed conformational studies of macrocyclic peptoids 61 63 and recently succeeded in the de novo design of potent inhibitors of β catenin. 64 Lim and coworkers have developed methodologies of screening a large library of macrocyclic peptoids 65 and produced inhibitors of Skp2/p300, which is a cancer related intracellular protein protein interaction. 66,67 Introduction of NSA residues to these macrocyclic oligo NSG 68 may further increase the conformational rigidity and accelerate peptoid drug discovery ability.…”

A rationally designed peptoid for the selective chelation of Zn2+ over Cu2+

“…Due to their ease of synthesis on a solid support, 10 sequence versatility and high stability, they exhibit great potential for application in catalysis, 11 self-assembly, 12 metal binding 13 and recognition, 14 and medicine. 15 Compared to small molecule chelators, peptoid chelators are advantageous because various metal-binding ligands and structural elements of choice can be incorporated within their scaffold with high sequence specicity, leading to control over a desired coordination geometry and complex stability. They include different N-donor ligands, many of which are the basis for systems used for Zn 2+ chelation and/or sensing.…”

An engineered antibody fragment targeting mutant β-catenin via major histocompatibility complex I neoantigen presentation

“…In addition to shallow binding sites, β-catenin binds multiple effector proteins, with both activators and repressors binding to the same site (12). Nevertheless, some groups have identified small molecules (13–22) or peptides/peptidomimetics (23–27) that directly bind β-catenin and show cellular inhibition of Wnt pathway signaling. However, the direct reliance of this phenotypic effect on small-molecule binding to β-catenin has yet to be established (11).…”