2. Academic Validation
  3. Leucine/Isoleucine Substitution Scanning of Tryptophan Residues to Reduce the Toxicity of β-Hairpin Peptide N2W2

Leucine/Isoleucine Substitution Scanning of Tryptophan Residues to Reduce the Toxicity of β-Hairpin Peptide N2W2

  • J Med Chem. 2025 Jul 10;68(13):13772-13792. doi: 10.1021/acs.jmedchem.5c00665.
Beibei Li 1,  Pengyi Yan 1,  Yao Liu 1,  Xu Ouyang 1,  Qingyang Xu 1,  Jingying Zhang 1,  Zufang Ba 1,  Jie Liu 1,  Yu Wang 1,  Tingting Yang 1,  Xueting Liu 1,  Zhongwei Yu 1,  Bingqian Ren 1,  Liru Yuan 1,  Yuhuan Zhao 1,  Chao Zhong 1 2,  Hui Liu 1 2,  Yun Zhang 1 2,  Sanhu Gou 1 2,  Jingman Ni 1 3 2
Affiliations

Affiliations

  • 1 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Institute of Pharmaceutics, School of Pharmacy, and Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, P. R. China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. Beijing 100050, P. R. China.
  • 3 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao 999078, P. R. China.
PMID: 40550734 DOI: 10.1021/acs.jmedchem.5c00665
Abstract

The unique bactericidal mechanism of antimicrobial peptides (AMPs) significantly reduces the likelihood of pathogenic bacteria developing resistance to them. However, AMPs exhibiting high antimicrobial activity are often associated with significant toxicity. In our prior studies, the peptide N2W2 (WKWKWWKWKW-NH2) exhibited potent antimicrobial activity but also high toxicity. In this study, the tryptophan of N2W2 was replaced with leucine or isoleucine, and the impact of amino acid substitutions at various positions on the SAR was examined. The analogs, especially those with terminal amino acid substitutions, maintained the potent antimicrobial activity of N2W2 while significantly lowering its toxicity, attributed to distinct changes in their secondary structure under varying membrane conditions. Peptide IL exhibited the highest therapeutic index, and its enantiomer D-IL demonstrated potent Antibacterial activity, minimal cytotoxicity, and exceptional stability. In conclusion, this study offers a simple strategy to minimize the toxicity of AMPs, thereby facilitating their clinical translation as Antibacterial agents.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P11583
    Antimicrobial Peptide