Structural optimization of reversible dibromomaleimide peptide stapling. Issue 1 (20th March 2020)

• Record Type: Journal Article
• Authors: Lindsey‐Crosthwait, Ayanna; Rodriguez‐Lema, Diana; Walko, Martin; Pask, Christopher M.; Wilson, Andrew J.
• Other Names: Jamieson Andrew G. guestEditor.
• Is Part Of: Peptide science. Volume 113:Issue 1(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-03-20
• Subjects: constrained peptides -- protein‐protein interactions -- dibromomaleimide -- peptide conformation; Peptides -- Periodicals; 572.6505
• DOI: 10.1002/pep2.24157
• Languages: English
• ISSNs: 2475-8817

Abstract

Abstract: Methods to constrain peptides in a bioactive α‐helical conformation for inhibition of protein‐protein interactions represent an ongoing area of investigation in chemical biology. Recently, the first example of a reversible "stapling" methodology was described which exploits native cysteine or homocysteine residues spaced at the i and i + 4 positions in a peptide sequence together with the thiol selective reactivity of dibromomaleimides (a previous study). This manuscript reports on the optimization of the maleimide based constraint, focusing on the kinetics of macrocyclization and the extent to which helicity is promoted with different thiol containing amino acids. The study identified an optimal stapling combination of X 1 = L‐Cys and X 5 = L‐ h Cys in the context of the model peptide Ac‐X1 AAAX5 ‐NH2, which should prove useful in implementing the dibromomaleimide stapling strategy in peptidomimetic ligand discovery programmes. Abstract :