C-terminal modification of a de novo designed antimicrobial peptide via capping of macrolactam rings

Ping Zeng; Qipeng Cheng; Lanhua Yi; Sharon Shui Yee Leung; Sheng Chen; Kin-Fai Chan; Kwok-Yin Wong

doi:10.1016/j.bioorg.2022.106251

C-terminal modification of a de novo designed antimicrobial peptide via capping of macrolactam rings

Bioorg Chem. 2023 Jan:130:106251. doi: 10.1016/j.bioorg.2022.106251. Epub 2022 Nov 5.

Authors

Ping Zeng¹, Qipeng Cheng², Lanhua Yi³, Sharon Shui Yee Leung⁴, Sheng Chen⁵, Kin-Fai Chan⁶, Kwok-Yin Wong⁷

Affiliations

¹ State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong; School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong.
² State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
³ Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong; College of Food Science, Southwest University, Chongqing, PR China.
⁴ School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong.
⁵ Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong. Electronic address: shechen@cityu.edu.hk.
⁶ State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong. Electronic address: kf.chan@polyu.edu.hk.
⁷ State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong. Electronic address: kwok-yin.wong@polyu.edu.hk.

PMID: 36370649
DOI: 10.1016/j.bioorg.2022.106251

Abstract

In this work, by capping a macrolactam ring at the C-terminus of a de novo-designed peptide, namely zp80, we have constructed a small peptide library via the solid phase peptide synthesis for screening. Eight peptides bearing different aspartic acid-rich macrolactam rings but the same linear (IIRR)₄ unit exhibited improved antibacterial activities, hemolytic activity, and selectivity index. Mechanistic studies revealed that they could destroy the integrity of bacterial envelope, leading to cytoplasm leakage and rapid dissipation of membrane potential. One of these peptides, zp90 with a macrolactam ring of (KaDGD), demonstrated preferential interaction with calcium ions at a stoichiometric ratio of 1:1, promoting the affinity of designed peptides to bacterial membrane. Overall, this work provides a feasible strategy for medicinal chemists to further develop potent, selective, and multifunctional de novo-designed antimicrobial peptides.

Keywords: Antimicrobial peptide; Calcium ion-binding affinity; Macrolactam ring; Membrane potential; Selectivity index.

Publication types

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

MeSH terms

Anti-Bacterial Agents / pharmacology
Antimicrobial Cationic Peptides* / pharmacology
Antimicrobial Peptides*
Bacteria
Microbial Sensitivity Tests
Structure-Activity Relationship

Substances

Antimicrobial Cationic Peptides
Antimicrobial Peptides
Anti-Bacterial Agents