Towards “bionic” proteins: replacement of continuous sequences from HIF-1α with proteomimetics to create functional p300 binding HIF-1α mimics

Abstract

An extended sequence of α-amino acids in HIF-1α is replaced with a non-natural topographical mimic of an α-helix comprised from an aromatic oligoamide to reproduce its p300 recognition properties.

Hypoxia inducible factor (HIF) as a model for studying inhibition of protein–protein interactions

“…To circumvent this deficiency we created hybrid structures comprising a peptide segment (from helix 2 of HIF-1α) and the original proteomimetic compound (mimicking helix 3 of HIF-1α) in an approach we referred to as a “bionic protein”. 128 Although the potency of the hybrid was slightly diminished, it was comparable in potency to the helix 2–3 peptide sequence upon which it was based and crucially the p53/ h DM2 inhibition was diminished to a greater extent thus improving selectivity. This is also the first example of functionally indistinguishable incorporation of a topographical helix mimetic into a peptide sequence.…”

Control of conformation in α-helix mimicking aromatic oligoamide foldamers through interactions between adjacent side-chains

“…35 Our group previously reported a series of aromatic oligoamide scaffolds designed to mimic the α-helix and inhibit α-helix mediated protein-protein interactions. [36][37][38][39] For the 2-and 3-Oalkylated scaffolds, these oligomers adopt an extended conformation determined by the trans configuration of the amide bond and in which rotation around the Ar-CO/NH axes is restricted by S (6) or S(5) intramolecular hydrogen bonding respectively ( Fig. 1a for an illustration of the 3-O-alkylated scaffolds).…”

Design, Synthesis and Docking of Linear and Hairpin‐Like Alpha Helix Mimetics Based on Alkoxylated Oligobenzamide

“…Due to its potential significance, non‐peptidic small molecule α‐helix mimetics have received considerable interest in the modulation of protein‐protein interactions in recent years. Hamilton, Wilson and other groups have designed and synthesized a number of small molecule α‐helix mimetics and some of these have proved to potently inhibit specific PPIs.…”