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Structural optimization of reversible dibromomaleimide peptide stapling.

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-hCys in the context of the model peptide Ac-X₁AAAX₅-NH₂, which should prove useful in implementing the dibromomaleimide stapling strategy in peptidomimetic ligand discovery programmes.

SUBMITTER: Lindsey-Crosthwait A

PROVIDER: S-EPMC8650577 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Structural optimization of reversible dibromomaleimide peptide stapling.

Lindsey-Crosthwait Ayanna A Rodriguez-Lema Diana D Walko Martin M Pask Christopher M CM Wilson Andrew J AJ

Peptide science (Hoboken, N.J.) 20200320 1

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 ...[more]

PMID: 34938942

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