Cell-Permeable Peptide Inhibitors of the p53-hDM2 Interaction via Foldamer Helix Mimicry and Bis-Thioether Stapling.

Combining helical foldamers with α-peptides can produce α-helix mimetics with a reduced peptide character and enhanced resistance to proteolysis. Previously, we engineered a hybrid peptide-oligourea sequence replicating the N-terminal α-helical domain of p53 to achieve high affinity binding to hDM2. Here, we further advance this strategy by combining the foldamer approach with side chain cross-linking to create more constrained cell-permeable inhibitors capable of effectively engaging the target within cells.

Guanidinium-Stapled Helical Peptides for Targeting Protein-Protein Interactions.

Peptide stapling has emerged as a versatile approach in drug discovery to reinforce secondary structure elements especially α-helices and improve properties of linear bioactive peptides. Inspired by the prevalence of arginine in protein-protein and protein-DNA interfaces, we investigated guanidinium-stapling as a means to constrain helical peptides. Guanidinium stapling was readily achieved on solid support, utilizing two orthogonally protected lysine or unatural α-amino acid residues with an amino function.

Short Oligourea Foldamers as N- or C-Caps for Promoting α-Helix Formation in Water.

While foldamers have been extensively studied as protein mimics and especially as α-helix mimics, their use as capping motif to enhance α-helix propensity remains comparatively much limited. In this study, we leverage the structural similarities between urea-based helical foldamers and α-helix to investigate the efficacy of oligoureas as N- or C-caps for reinforcing α-helical structures in water. Short oligoureas, comprising 3 to 4 residues, were strategically introduced at the N- or C-terminus of two peptide sequences (S-peptide and an Ala-rich model sequence).

Peptide-Based Covalent Inhibitors Bearing Mild Electrophiles to Target a Conserved His Residue of the Bacterial Sliding Clamp.

Peptide-based covalent inhibitors targeted to nucleophilic protein residues have recently emerged as new modalities to target protein-protein interactions (PPIs) as they may provide some benefits over more classic competitive inhibitors. Covalent inhibitors are generally targeted to cysteine, the most intrinsically reactive amino acid residue, and to lysine, which is more abundant at the surface of proteins but much less frequently to histidine. Herein, we report the structure-guided design of targeted covalent inhibitors (TCIs) able to bind covalently and selectively to the bacterial sliding clamp (SC), by reacting with a well-conserved histidine residue located on the edge of the peptide-binding pocket.

Oligourea helix bundle binds detergents with diverse polar head groups.

Here we report a series of crystal structures (and accompanying biophysical data) of an array of diverse detergent guests bound to an oligourea foldamer helix bundle. These results significantly increase our structural and chemical understanding of aqueous guest recognition by oligourea foldamers and will aid the design of further functionalised oligourea-based self-assemblies.

Synthesis and Crystallographic Characterization of Helical Hairpin Oligourea Foldamers.

Invited for the cover of this issue is the group of Gilles Guichard at the University of Bordeaux. The image depicts sketches and technical drawing tools to illustrate the creation and precise characterization of foldamer tertiary structures. Read the full text of the article at 10.

Unexpected binding modes of inhibitors to the histone chaperone ASF1 revealed by a foldamer scanning approach.

In the search for foldamer inhibitors of the histone chaperone ASF1, we explored the possibility of substituting four α-residues (≈one helix turn) by 3-urea segments and scanned the sequence of a short α-helical peptide known to bind ASF1. By analysing the impact of the different foldamer replacements within the peptide chain, we uncovered new binding modes of the peptide-urea chimeras to ASF1.

Synthesis and Crystallographic Characterization of Helical Hairpin Oligourea Foldamers.

Oligomers designed to form a helix-turn-helix super-secondary structure have been prepared by covalently bridging aliphatic oligourea foldamer helices with either rigid aromatic or more flexible aliphatic spacers. The relative helix orientation in these dimers was investigated at high resolution using X-ray diffraction analysis. In several cases, racemic crystallography was used to facilitate crystallization and structure determination.

PSL Chemical Biology Symposia Third Edition: A Branch of Science in its Explosive Phase.

This symposium is the third PSL (Paris Sciences & Lettres) Chemical Biology meeting (2016, 2019, 2023) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette (2013, 2014), under the directorship of Professor Max Malacria, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting.

Cell-free synthesis of amyloid fibrils with infectious properties and amenable to sub-milligram magic-angle spinning NMR analysis.

Structural investigations of amyloid fibrils often rely on heterologous bacterial overexpression of the protein of interest. Due to their inherent hydrophobicity and tendency to aggregate as inclusion bodies, many amyloid proteins are challenging to express in bacterial systems. Cell-free protein expression is a promising alternative to classical bacterial expression to produce hydrophobic proteins and introduce NMR-active isotopes that can improve and speed up the NMR analysis.

Hexafluoroisobutylation of enolates through a tandem elimination/allylic shift/hydrofluorination reaction.

The isobutyl side chain is a highly prevalent hydrophobic group in drugs, and it notably constitutes the side chain of leucine. Its replacement by a hexafluorinated version containing two CF groups may endow the target compound with new and advantageous properties, yet this modification remains overlooked due to the absence of a general and practical synthetic methodology. Herein, we report the first general method to introduce the hexafluoroisobutyl group into ketoesters, malonates, 1,3-diketones, Schiff base esters and malononitrile.

Reaching High Stereoselectivity and Activity in Organocatalyzed Ring-Opening Polymerization of Racemic Lactide by the Combined Use of a Chiral (Thio)Urea and a -Heterocyclic Carbene.

Stereochemical control during polymerization is a key strategy of polymer chemistry to achieve semicrystalline engineered plastics. The stereoselective ring-opening polymerization (ROP) of racemic lactide (-LA), which can lead to highly isotactic polylactide (PLA), is one of the emblematic examples in this area. Surprisingly, stereoselective ROP of -LA employing chiral organocatalysts has been under-leveraged.

Adaptive Binding of Alkyl Glycosides by Nonpeptidic Helix Bundles in Water: Toward Artificial Glycolipid Binding Proteins.

Amphipathic water-soluble helices formed from synthetic peptides or foldamers are promising building blocks for the creation of self-assembled architectures with non-natural shapes and functions. While rationally designed artificial quaternary structures such as helix bundles have been shown to contain preformed cavities suitable for guest binding, there are no examples of adaptive binding of guest molecules by such assemblies in aqueous conditions. We have previously reported a foldamer 6-helix bundle that contains an internal nonpolar cavity able to bind primary alcohols as guest molecules.

Insight into Substrate Recognition by Urea-Based Helical Foldamer Catalysts Using a DFT Global Optimization Approach.

Peptides and foldamers have recently gained increasing attention as chiral catalysts to achieve challenging (asymmetric) transformations. We previously reported that short helically folded aliphatic oligoureas in combination with achiral Brønsted bases are effective H-bonding catalysts for C-C bond-forming reactions─i.e.

Block Copolymer Synthesis by a Sequential Addition Strategy from the Organocatalytic Group Transfer Polymerization of Methyl Methacrylate to the Ring-Opening Polymerization of Lactide.

Sequential block copolymerization involving comonomers belonging to different classes, e.g., a vinyl-type monomer and a heterocycle, is a challenging task in macromolecular chemistry, as corresponding propagating species do not interconvert easily from one to the other by crossover reactions.

Design of Oligourea-Based Foldamers with Antibacterial and Antifungal Activities.

There is an urgent need to develop new therapeutic strategies to fight the emergence of multidrug resistant bacteria. Many antimicrobial peptides (AMPs) have been identified and characterized, but clinical translation has been limited partly due to their structural instability and degradability in physiological environments. The use of unnatural backbones leading to foldamers can generate peptidomimetics with improved properties and conformational stability.

Iterative Structure-Based Optimization of Short Peptides Targeting the Bacterial Sliding Clamp.

The bacterial DNA sliding clamp (SC), or replication processivity factor, is a promising target for the development of novel antibiotics. We report a structure-activity relationship study of a new series of peptides interacting within the SC (SC) binding pocket. Various modifications were explored including N-alkylation of the peptide bonds, extension of the N-terminal moiety, and introduction of hydrophobic and constrained residues at the C-terminus.

Crystal structures capture multiple stoichiometric states of an aqueous self-assembling oligourea foldamer.

We report here an oligourea foldamer able to self-assemble in aqueous conditions into helix bundles of multiple stoichiometries. Importantly, we report crystal structures of several of these stoichiometries, providing a series of high-resolution snap-shots of the structural polymorphism of this foldamer and uncovering a novel self-assembly.

Urea based foldamers.

N,N'-linked oligoureas are a class of enantiopure, sequence-defined peptidomimetic oligomers without amino acids that form well-defined and predictable helical structures akin to the peptide α-helix. Oligourea-based foldamers combine a number of features-such as synthetic accessibility, sequence modularity, and folding fidelity-that bode well for their use in a range of applications from medicinal chemistry to catalysis. Moreover, it was recently recognized that this synthetic helical backbone can be combined with regular peptides to generate helically folded peptide-oligourea hybrids that display additional features in terms of helix mimicry and protein-surface recognition properties.

Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity.

Sequence-specific oligomers with predictable folding patterns, i.e., foldamers, provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions.

A chiral thiourea and a phosphazene for fast and stereoselective organocatalytic ring-opening-polymerization of racemic lactide.

Control of stereoregularity is inherent to precision polymerization chemistry for the development of functional materials. A prototypal example of this strategy is the ring-opening polymerization (ROP) of racemic lactide (rac-LA), a bio-sourced monomer. Despite significant advances in organocatalysis, stereoselective ROP of rac-LA employing chiral organocatalysts remains unexplored.

Delivery of siRNA by tailored cell-penetrating urea-based foldamers.

Cell-penetrating foldamers (CPFs) have recently shown promise as efficient and safe nucleic acid delivery systems. However, the application of CPFs to siRNA transport remains scarce. Here, we report helical CPFs tailored with specific end-groups (pyridylthio- or n-octyl-ureas) as effective molecular systems in combination with helper lipids to intracellularly deliver biologically-relevant siRNA.

Structural Basis for α-Helix Mimicry and Inhibition of Protein-Protein Interactions with Oligourea Foldamers.

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).