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N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists
Author(s) -
Baggio Carlo,
Udompholkul Parima,
Gambini Luca,
Jossart Jennifer,
Salem Ahmed F.,
Håkansson Maria,
Perry J. Jefferson P.,
Pellecchia Maurizio
Publication year - 2020
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13661
Subject(s) - covalent bond , chemistry , peptide , residue (chemistry) , stereochemistry , combinatorial chemistry , biophysics , biochemistry , organic chemistry , biology
Recently, it was reported that tetrapeptides cyclized via lactam bond between the amino terminus and a glutamic residue in position 4 (termed here N‐lock ) can nucleate helix formation in longer peptides. We applied such strategy to derive N‐locked covalent BH3 peptides that were designed to selectively target the anti‐apoptotic protein Bfl‐1. The resulting agents were soluble in aqueous buffer and displayed a remarkable (low nanomolar) affinity for Bfl‐1 and cellular activity. The crystal structure of the complex between such N‐locked covalent peptide and Bfl‐1 provided insights on the geometry of the N‐locking strategy and of the covalent bond between the agent and Bfl‐1.