2. Academic Validation
  3. Development of New Antimicrobial Peptides by Integrating Structural Motifs from Microbial-Derived Cyclic Lipopeptides

Development of New Antimicrobial Peptides by Integrating Structural Motifs from Microbial-Derived Cyclic Lipopeptides

  • J Med Chem. 2025 Jun 26;68(12):12573-12592. doi: 10.1021/acs.jmedchem.5c00331.
Tingting Yang 1,  Yu Wang 1,  Xu Ouyang 1,  Yao Liu 1,  Beibei Li 1,  Zufang Ba 1,  Yuhuan Zhao 1,  Pengyi Yan 1,  Bingqian Ren 1,  Zhongwei Yu 1,  Xueting Liu 1,  Chao Zhong 1 2,  Hui Liu 1 2,  Yun Zhang 1 2,  Sanhu Gou 1 2,  Jingman Ni 1 2 3
Affiliations

Affiliations

  • 1 Institute of Pharmaceutics, School of Pharmacy, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, and Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, P. R. China.
  • 2 Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Xian Nong Tan Street, 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: 40522864 DOI: 10.1021/acs.jmedchem.5c00331
Abstract

Microbial-derived cyclic-lipid antimicrobial peptides (CLAMPs) exhibit significant toxicity, which hinders their wide application in clinical practice. However, such AMPs generally possess high antimicrobial activity and high metabolic stability. The superiority of their molecular structures merits summarization and can be utilized in the design of novel AMPs. Therefore, a heptameric CLAMP template was designed from scratch in this study, with the general formula: R-Dab-(x)-DTyr-cyclo[Lys-y-y-Trp-z-z-Glu]. Through modifying the N-terminal acyl group and Amino acids at key positions inside and outside the ring, new CLAMPs with high antimicrobial activity, low toxicity, and high stability were screened out. Among these, the newly optimized CLAMPs, CyLip-10 and CyLip-20, stand out for their broad-spectrum antimicrobial efficacy, low hemolytic activity, and excellent stability. Additionally, they have good safety and antimicrobial activity in vivo. In summary, designing novel CLAMPs based on those derived from Microorganisms is feasible and effective.

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