Structural Basis for α‐Helix Mimicry and Inhibition of Protein–Protein Interactions with Oligourea Foldamers

Abstract

Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence‐based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein–protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X‐ray structures of peptide–oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer‐based disruptors of PPIs in the context of peptide lead optimization.

Design of Protein Segments and Peptides for Binding to Protein Targets

“…The abundance of helical motifs at protein-protein interfaces (Figure 7) [126] created a large space for the use of α -helix mimicking foldamers with many successful examples reported to date. One successful example of α-helix mimicry are peptide-oligourea hybrids, used to inhibit a variety of proteins such as MDM2 and vitamin D receptors [127]. Another example is the use of Terphenyl scaffolds as helix mimetics to generate binders against Bcl-x L and Bak interactions [128].…”

Urea based foldamers

“…The ability to synthesize diverse, sequence-specific oligoureas that fold with a high degree of predictability has stimulated the interest of our group and others to endow urea-based foldamers with function. Examples of applications reported for urea-based foldamers range from bioactive peptide mimics (Fremaux, Venin, Mauran, Zimmer, Guichard, et al, 2019) including modulators of proteinprotein interactions (Cussol et al, 2021) to quaternary structures (Collie et al, 2015) and from electron transfer(Pulka-Ziach & Sęk, 2017) to catalysis (Bécart et al, 2017). Some of these applications are discussed in more detail below.…”

“…However, one difficulty associated with the use of foldamers as α-helix mimics is to select and arrange key side chains on the surface of the foldamer so as to maintain key contacts with the target. By selecting ubiquitin ligase MDM2, vitamin D receptor and histone chaperon ASF1 as targets, we have designed peptide/oligourea chimeras that retain affinity for their protein target while showing increased resistance to proteolysis (Cussol et al, 2021;Mbianda et al, 2020). X-ray structure analysis of several of these peptide-oligourea hybrids bound to their respective protein targets confirms the high degree of α-helix mimicry that can be achieved with oligoureas and reveals general principles that should enable the design of more potent peptide-based inhibitors of protein-protein interactions.…”

“…Thus far, the best conditions identified for on-resin reduction of azido-terminated oligoureas involve the use of trimethylphosphine with microwave assistance. This method is compatible with automation and parallel synthesis and is now routinely used in our laboratory to prepare oligoureas and related peptide-oligourea hybrids (Antunes, Douat, & Guichard, 2016;Cussol et al, 2021). The detailed synthetic procedures are reported in section 5.3.…”

Design, synthesis, and structural characterization of helix-forming aliphatic homo-δ-peptides based on conformational restriction due to the structural characteristics of cyclopropane

“…Many artificial oligomers, called foldamers, 1-2 that self-organize into a specific secondary structure usually mimicking or expanding natural secondary structures of α-peptides, have been developed over the last several decades. [3][4][5][6][7][8] Peptide foldamers have a wide range of applications. [9][10][11][12][13] Significant studies of foldamers comprising homo-oligomers of β-and γamino acids (β-and γ-peptides) with a structurally restricted backbone triggered the recent intense interest in foldamer research.…”