Disulfide Click Reaction for Stapling of S-terminal Peptides

Qing Yu; Leiyang Bai; Xuefeng Jiang

doi:10.1002/anie.202314379

Disulfide Click Reaction for Stapling of S-terminal Peptides

Qing Yu
, Leiyang Bai
, Xuefeng Jiang^*

^*Corresponding author for this work

School of Chemistry and Molecular Engineering

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

A disulfide click strategy is disclosed for stapling to enhance the metabolic stability and cellular permeability of therapeutic peptides. A 17-membered library of stapling reagents with adjustable lengths and angles was established for rapid double/triple click reactions, bridging S-terminal peptides from 3 to 18 amino acid residues to provide 18- to 48-membered macrocyclic peptides under biocompatible conditions. The constrained peptides exhibited enhanced anti-HCT-116 activity with a locked α-helical conformation (IC₅₀=6.81 μM vs. biological incompetence for acyclic linear peptides), which could be unstapled for rehabilitation of the native peptides under the assistance of tris(2-carboxyethyl)phosphine (TCEP). This protocol assembles linear peptides into cyclic peptides controllably to retain the diverse three-dimensional conformations, enabling their cellular uptake followed by release of the disulfides for peptide delivery.

Original language	English
Article number	e202314379
Journal	Angewandte Chemie - International Edition
Volume	62
Issue number	52
DOIs	https://doi.org/10.1002/anie.202314379
State	Published - 21 Dec 2023

Keywords

Cyclic Peptides
Disulfide Stapling Reagents
Peptide Delivery
Reversible Stapling
α-Helicity

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10.1002/anie.202314379

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title = "Disulfide Click Reaction for Stapling of S-terminal Peptides",

abstract = "A disulfide click strategy is disclosed for stapling to enhance the metabolic stability and cellular permeability of therapeutic peptides. A 17-membered library of stapling reagents with adjustable lengths and angles was established for rapid double/triple click reactions, bridging S-terminal peptides from 3 to 18 amino acid residues to provide 18- to 48-membered macrocyclic peptides under biocompatible conditions. The constrained peptides exhibited enhanced anti-HCT-116 activity with a locked α-helical conformation (IC50=6.81 μM vs. biological incompetence for acyclic linear peptides), which could be unstapled for rehabilitation of the native peptides under the assistance of tris(2-carboxyethyl)phosphine (TCEP). This protocol assembles linear peptides into cyclic peptides controllably to retain the diverse three-dimensional conformations, enabling their cellular uptake followed by release of the disulfides for peptide delivery.",

keywords = "Cyclic Peptides, Disulfide Stapling Reagents, Peptide Delivery, Reversible Stapling, α-Helicity",

author = "Qing Yu and Leiyang Bai and Xuefeng Jiang",

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year = "2023",

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doi = "10.1002/anie.202314379",

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T1 - Disulfide Click Reaction for Stapling of S-terminal Peptides

AU - Yu, Qing

AU - Bai, Leiyang

AU - Jiang, Xuefeng

PY - 2023/12/21

Y1 - 2023/12/21

N2 - A disulfide click strategy is disclosed for stapling to enhance the metabolic stability and cellular permeability of therapeutic peptides. A 17-membered library of stapling reagents with adjustable lengths and angles was established for rapid double/triple click reactions, bridging S-terminal peptides from 3 to 18 amino acid residues to provide 18- to 48-membered macrocyclic peptides under biocompatible conditions. The constrained peptides exhibited enhanced anti-HCT-116 activity with a locked α-helical conformation (IC50=6.81 μM vs. biological incompetence for acyclic linear peptides), which could be unstapled for rehabilitation of the native peptides under the assistance of tris(2-carboxyethyl)phosphine (TCEP). This protocol assembles linear peptides into cyclic peptides controllably to retain the diverse three-dimensional conformations, enabling their cellular uptake followed by release of the disulfides for peptide delivery.

AB - A disulfide click strategy is disclosed for stapling to enhance the metabolic stability and cellular permeability of therapeutic peptides. A 17-membered library of stapling reagents with adjustable lengths and angles was established for rapid double/triple click reactions, bridging S-terminal peptides from 3 to 18 amino acid residues to provide 18- to 48-membered macrocyclic peptides under biocompatible conditions. The constrained peptides exhibited enhanced anti-HCT-116 activity with a locked α-helical conformation (IC50=6.81 μM vs. biological incompetence for acyclic linear peptides), which could be unstapled for rehabilitation of the native peptides under the assistance of tris(2-carboxyethyl)phosphine (TCEP). This protocol assembles linear peptides into cyclic peptides controllably to retain the diverse three-dimensional conformations, enabling their cellular uptake followed by release of the disulfides for peptide delivery.

KW - Cyclic Peptides

KW - Disulfide Stapling Reagents

KW - Peptide Delivery

KW - Reversible Stapling

KW - α-Helicity

UR - https://www.scopus.com/pages/publications/85177587216

U2 - 10.1002/anie.202314379

DO - 10.1002/anie.202314379

M3 - 文章

C2 - 37950389

AN - SCOPUS:85177587216

SN - 1433-7851

VL - 62

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 52

M1 - e202314379

ER -

Disulfide Click Reaction for Stapling of S-terminal Peptides

Abstract

Keywords

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