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N-locking stabilization of covalent helical peptides: Application to Bfl-1 antagonists.

ABSTRACT: 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.

SUBMITTER: Baggio C

PROVIDER: S-EPMC7568863 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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N-locking stabilization of covalent helical peptides: Application to Bfl-1 antagonists.

Baggio Carlo C Udompholkul Parima P Gambini Luca L Jossart Jennifer J Salem Ahmed F AF Håkansson Maria M Perry J Jefferson P JJP Pellecchia Maurizio M

Chemical biology & drug design 20200120 4

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 struct ...[more]

PMID: 31898401

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