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 Oligourea-Based Foldamers with Antibacterial and Antifungal Activities

“…In both sequences, polar and cationic residues were concentrated in the α-peptide segment whereas hydrophobic side chains (Ala u /Trp u in OL-6 versus Val u /Trp u in OL-7 ) were clustered in the oligourea part at the C-terminus of the peptide segment by analogy to cationic amphiphilic block copolymers [ 34 ]. These two hybrid sequences were produced using an azide-type chemistry for the foldamer fragment synthesis combined with a Fmoc-chemistry for the pentapeptide installation on solid support [ 35 ].…”

“…Amphipathic hybrid peptide–oligourea foldamers OL-6 and OL-7 were prepared following an azide-type chemistry for the urea segment and a Fmoc-chemistry for the peptide segment according to a recent literature procedure [ 35 ]. As an example, OL-7 was synthesized on a 50 μmol scale starting from commercially available MBHA-Rink amide resin.…”

Bispidine as a β-strand nucleator: from a β-arch to self-assembled cages and vesicles

“…Many studies have already explored α-helix mimics while β-sheet mimics are less studied because of the lack of good chemical models. [6][7][8][9] Similarly, helical PPIs have been extensively targeted, while inhibition of β-sheet interface is very limited. 10 Peptidomimetic foldamers that can mimic βsheet interface and form soluble β-sheet aggregates can be excellent candidates for therapeutic intervention against protein aggregation.…”

“…Nucleation of secondary structure is achieved by the introduction of a rigid unit that favors the initial hydrogen-bonding pattern of α-helix or β-strand as per the nucleating preference of the scaffold. [6][7][8][9][16][17][18] However, there are limited examples of isolated β-strands. Most of the designed scaffolds act by facilitating initial hydrogen bonding to form a sheet that further propagates the β-sheet structure.…”

Deep Sequencing of a Systematic Peptide Library Reveals Conformationally‐Constrained Protein Interface Peptides that Disrupt a Protein‐Protein Interaction

“…Protein domain mimics that incorporate a secondary structure to display hotspot residues in the proper orientation for interaction with the target have been successfully used to develop PPI inhibitors [4,10] . Examples of this include the development of α‐helix mimics that contain hotspot residues displayed on one face of the helix [4,18–20] . Similarly, macrocycles have been used to mimic loop structures in an interface, [21,22] and tertiary structure mimics have been developed to take advantage of the fact that hotspot residues are often present on multiple secondary structures [10,23–25] …”