Foldamers in Medicinal Chemistry

International audienc

Structures repliées et dynamique conformationnelle de peptidomimétiques à base d'oligoamides d'Aza-aromatiques

Des oligoamides aromatiques de synthèse ont été conçus pour adopter des conformations hélicoïdales bien définies, stabilisées par la formation de liaisons hydrogène intramoléculaires. Ces architectures ont été caractérisées dans le solide par diffraction des rayons X. Une analyse conformationnelle par RMN 2D, similaire à celle développée pour les peptides, a permis de confirmer la conformation hélicoïdale de ces brins moléculaires en solution. Ces structures repliées peuvent subir des modifications conformationnelles de large amplitude – dépliement, repliement- contrôlées par le pH et réversibles. Le sens d'hélicité de ces oligoamides peut être contrôlé par interaction intramoléculaire en introduisant un groupe chiral à l'extrémité du brin. Cette induction de chiralité semble dirigée principalement par des phénomènes stériques. La transmission du sens d'hélicité à travers des espaceurs placés entre deux segments hélicoïdaux d'oligoamide aromatique a permis de mettre en évidence la rétention ou l'inversion du sens d'hélicité, ou simplement l'absence de communication entre les deux segments, suivant la nature de l'espaceur. Une stratégie basée sur un encombrement stérique mutuel a conduit à la construction de la première hélice méso conçue de façon rationnelle.Pyridine and quinoline-derived oligoamide foldamers have been designed to adopt welldefined helical conformations stabilized by intramolecular hydrogen bonds. These helical structures have been characterized in the solid state by single crystal X-ray diffraction. In solution, NMR experiments similar to those developed for solving the structures of pepdides have fully demonstrated that the solution conformations are identical to those observed in the solid state. Conformational transitions of large amplitude, such as unfolding and re-folding, can be triggered upon partial and selective protonation or full protonation of the oligoamides. Intramolecular chiral induction of the handedness has been observed in helical aromatic oligoamides bearing asymmetric centers at the end of the strand, and seems to be directed by steric phenomena. Transmission of the handedness across a spacer placed between two helical segments leads to retention or inversion of the handedness, or simply to the absence of communication between the two segments, depending on the topology of the spacer. A strategy based on mutual steric exclusion has allowed the construction of the first designed meso-helices

Toward large tubular helices based on the polymerization of tri(benzamide)s

Herein we present the synthesis and polycondensation of mono- and di-N-protected, bis-substituted tri(benzamide)s with the aim to create large, tubular helices. We synthesized 2,4-dimethoxy and 2,5-bis-TEGylated aminobenzoic acid derivatives as bent and linear monomers and introduced p-methoxybenzyl (PMB) amide protecting groups to the oligobenzamide backbone. An iterative coupling strategy allowed for sequence control, giving rise to oligomers consisting of one bent and two linear monomers. The resulting meta-para-para-linked aromatic trimers carried either one or two PMB-protecting groups. With high organosolubility and flexibility, this synthetic strategy generated suitable precursors for subsequent polycondensation reactions. After polymerization, treatment with acid triggered the cleavage of the N-protecting groups. We hypothesize that the hydrogen bonding pattern generated along the polyaramide backbone could lead to the formation of a helical polymer. A drastic change in hydrodynamic volume was observed by gel permeation chromatography and dissolution in a chiral solvent lead to the observation of a circular dichroism signal for this polymer. The results of the polycondensations of N-protected oligobenzamides are reported herein. The formation of macrocycles as well as polymers could also be observed, giving a highly interesting insight into the underlying mechanism of the polycondensation of flexible, oligobenzamide-based oligomer

Structural Basis for alpha-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). 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

Enzyme-Catalyzed Macrocyclization of Long Unprotected Peptides

A glutathione S-transferase (GST) catalyzed macrocyclization reaction for peptides up to 40 amino acids in length is reported. GST catalyzes the selective SNAr reaction between an N-terminal glutathione (GSH, γ-Glu-Cys-Gly) tag and a C-terminal perfluoroaryl-modified cysteine on the same polypeptide chain. Cyclic peptides ranging from 9 to 24 residues were quantitatively produced within 2 h in aqueous pH = 8 buffer at room temperature. The reaction was highly selective for cyclization at the GSH tag, enabling the combination of GST-catalyzed ligation with native chemical ligation to generate a large 40-residue peptide macrocycle.Massachusetts Institute of Technology (MIT startup funds)National Institutes of Health (U.S.) (grant GM101762)Damon Runyon Cancer Research Foundation (Award)Sontag Foundation (Distinguished Scientist Award)Amgen Inc. (Summer Graduate Research Fellowship

X-ray Crystallographic Structure of an Artificial β-Sheet Dimer

This paper describes the X-ray crystallographic structure of a designed cyclic beta-sheet peptide that forms a well-defined hydrogen-bonded dimer that mimics beta-sheet dimers formed by proteins. The 54-membered ring macrocyclic peptide (1a) contains molecular template and turn units that induce beta-sheet structure in a heptapeptide strand that forms the dimerization interface. The X-ray crystallographic structure reveals the structures of the two "Hao" amino acids that help template the beta-sheet structure and the two delta-linked ornithine turn units that link the Hao-containing template to the heptapeptide beta-strand. The Hao amino acids adopt a conformation that resembles a tripeptide in a beta-strand conformation, with one edge of the Hao unit presenting an alternating array of hydrogen-bond donor and acceptor groups in the same pattern as that of a tripeptide beta-strand. The delta-linked ornithines adopt a conformation that resembles a hydrogen-bonded beta-turn, in which the ornithine takes the place of the i+1 and i+2 residues. The dimers formed by macrocyclic beta-sheet 1a resemble the dimers of many proteins, such as defensin HNP-3, the lambda-Cro repressor, interleukin 8, and the ribonuclease H domain of HIV-1 reverse transcriptase. The dimers of 1a self-assemble in the solid state into a barrel-shaped trimer of dimers in which the three dimers are arranged in a triangular fashion. Molecular modeling in which one of the three dimers is removed and the remaining two dimers are aligned face-to-face provides a model of the dimers of dimers of closely related macrocyclic beta-sheet peptides that were observed in solution

Structures repliées et dynamique conformationnelle de peptidomimétiques à base d'oligoamides d'aza-aromatiques

Des oligoamides aromatiques de synthèse ont été conçus pour adopter des conformations hélicoïdales bien définies, stabilisées par la formation de liaisons hydrogène intramoléculaires. Ces architectures ont été caractérisées dans le solide par diffraction des rayons X. Une analyse conformationnelle par RMN 2D, similaire à celle développée pour les peptides, a permis de confirmer la conformation hélicoïdale de ces brins moléculaires en solution. Ces structures repliées peuvent subir des modifications conformationnelles de large amplitude dépliement, repliement- contrôle es par le pH et réversibles. Le sens d'hélicité de ces oligoamides peut être contrôlé par interaction intramoléculaire en introduisant un groupe chiral à l'extrémité du brin. Cette induction de chiralité semble dirigée principalement par des phénomènes stériques. La transmission du sens d'hélicité à travers des espaceurs placés entre deux segments hélicoïdaux d'oligoamide aromatique a permis de mettre en évidence la rétention ou l'inversion du sens d'hélicité, ou simplement l'absence de communication entre les deux segments, suivant la nature de l'espaceur. Une stratégie basée sur un encombrement stérique mutuel a conduit à la construction de la première hélice méso conçue de façon rationnelleBORDEAUX1-BU Sciences-Talence (335222101) / SudocSudocFranceF