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

被引:31
作者
Cussol, Leonie [1 ]
Mauran-Ambrosino, Laura [1 ,2 ]
Buratto, Jeremie [1 ]
Belorusova, Anna Y. [3 ]
Neuville, Maxime [1 ,2 ]
Osz, Judit [3 ]
Fribourg, Sebastien [4 ]
Fremaux, Juliette [2 ]
Dolain, Christel [1 ]
Goudreau, Sebastien R. [2 ]
Rochel, Natacha [3 ]
Guichard, Gilles [1 ]
机构
[1] Univ Bordeaux, Inst Europeen Chim & Biol, Bordeaux INP, CBMN,CNRS,UMR 5248, 2 Rue Robert Escarpit, F-33607 Pessac, France
[2] Ureka Pharma SAS, 2 Rue Robert Escarpit, F-33607 Pessac, France
[3] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire IGBMC, INSERM, U1258,CNRS,UMR 7104, F-67404 Illkirch Graffenstaden, France
[4] Univ Bordeaux, ARNA Lab, INSERM, U1212,CNRS,UMR 5320, Bordeaux, France
关键词
foldamers; helical structures; oligoureas; protein– protein interactions; structure– activity relationships; D NUCLEAR RECEPTOR; PEPTIDES; DERIVATIVES; TARGETS; TIME;
D O I
10.1002/anie.202008992
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
引用
收藏
页码:2296 / 2303
页数:8
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