CUSSOL, Leonie; MAURAN-AMBROSINO, Laura; BURATTO, Jeremie; BELORUSOVA, Anna Y.; NEUVILLE, Maxime; OSZ, Judit; FRIBOURG, Sebastien; FREMAUX, Juliette; DOLAIN, Christel; GOUDREAU, Sebastien R.; ROCHEL, Natacha; GUICHARD, Gilles

doi:10.1002/anie.202008992

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CUSSOL, Leonie
Chimie et Biologie des Membranes et des Nanoobjets [CBMN]

MAURAN-AMBROSINO, Laura
Chimie et Biologie des Membranes et des Nanoobjets [CBMN]

BURATTO, Jeremie
Chimie et Biologie des Membranes et des Nanoobjets [CBMN]

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Angewandte Chemie-International Edition. 2021, vol. 60, n° 5, p. 2296-2303

Resumen en inglés

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.< Leer menos

Palabras clave en inglés

Peptidomimetics

Foldamers

Protein-protein interactions

Helical structures

Structure-activity relationships