Benzyl stapled modification and anticancer activity of antimicrobial peptide A4K14-Citropin 1.1

Huaxing Shen; Nan Zhang; Xianglong Kong; Nan Wang; Hong-Gang Hu; Wei Cong; Chao Liu

doi:10.1016/j.bmcl.2023.129499

Benzyl stapled modification and anticancer activity of antimicrobial peptide A4K14-Citropin 1.1

Bioorg Med Chem Lett. 2023 Nov 15:96:129499. doi: 10.1016/j.bmcl.2023.129499. Epub 2023 Oct 6.

Authors

Huaxing Shen¹, Nan Zhang¹, Xianglong Kong², Nan Wang¹, Hong-Gang Hu¹, Wei Cong³, Chao Liu⁴

Affiliations

¹ School of Medicine, Shanghai University, Shanghai 200444, China.
² School of Pharmacy, Weifang Medical University, Weifang 261053, PR. China.
³ School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address: viviencong@shu.edu.cn.
⁴ School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address: liuchao518@shu.edu.cn.

PMID: 37804993
DOI: 10.1016/j.bmcl.2023.129499

Abstract

A4K14-Citropin 1.1 (GLFAVIKKVASVIKGL-NH₂) is a derived antimicrobial peptide (AMP) with a more stable α-helical structure at the C-terminal compared to prototype Citropin 1.1 which was obtained from glandular skin secretions of Australian freetail lizards. In a previous report, A4K14-Citropin 1.1 has been considered as an anti-cancer lead compound. However, linear peptides are difficult to maintain stable secondary structure, resulted in poor pharmacokinetic properties. In this study, we designed and synthesized a series of benzyl-stapled derivatives of A4K14-Citropin 1.1. And their physical and chemical properties, as well as biological activity, were both explored. The result showed that AC-CCSP-2-o and AC-CCSP-3-o exhibited a higher degree of helicity and greater anti-cancer activity compared with the prototype peptide. Besides, there was no significant difference in the hemolytic effect between the stapled peptides and the prototype peptide. AC-CCSP-2-o and AC-CCSP-3-o could serve as promising anti-cancer lead compounds for the novel anti-cancer drug development.

Keywords: A4K14-Citropin 1.1; AMP; Anti-cancer activity; Antimicrobial peptide; Thiol-halogen click chemistry.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amphibian Proteins / chemistry
Antimicrobial Cationic Peptides* / chemistry
Antimicrobial Cationic Peptides* / pharmacology
Antimicrobial Peptides*
Protein Conformation, alpha-Helical
Protein Structure, Secondary

Substances

Antimicrobial Cationic Peptides
Antimicrobial Peptides
Amphibian Proteins