Improving the Stability and Anti-Infective Activity of Sea Turtle AMPs Using Multiple Structural Modification Strategies

  • J Med Chem. 2024 Dec 26;67(24):22104-22123. doi: 10.1021/acs.jmedchem.4c02039.
Zifan Ye  1  2 ,  Zhouye Xu  2 ,  Jianhong Ouyang  2 ,  Wenzhuang Shi  1  2 ,  Shuangyu Li  1  2 ,  Xu Wang  1  2 ,  Binjuan Lu  2 ,  Kang Wang  2 ,  Yipeng Wang  1  2  3
Affiliations
  • 1. Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong 264003, China.
  • 2. Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
  • 3. University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 39636182 DOI: 10.1021/acs.jmedchem.4c02039
Abstract

Antimicrobial peptides (AMPs) are regarded as promising candidates for combating antimicrobial resistance. Previously we identified an AMP named Cm-CATH2 from the green sea turtle, which exhibited potent Antibacterial activity and attractive potential in application. However, natural AMPs including Cm-CATH2 frequently suffer from structural instability and sensitivity to physiological conditions, limiting their effectiveness. Herein, we explored various strategies to enhance the efficacy and stability of Cm-CATH2, including peptide truncation, non-natural amino acid substitutions, disulfide bond-based cyclization, and stapled peptide techniques. The results demonstrated that the truncated NCM4 significantly improved the antimicrobial capability of Cm-CATH2 while also enhancing its anti-inflammatory and antibiofilm activities with minimal cytotoxicity. Further ornithine-substituted peptide oNCM markedly enhanced the stability of NCM4 without compromising its antimicrobial efficacy. This study successfully designed a lead peptide oNCM with significant development potential, while providing valuable insights into the advantages and limitations associated with diverse strategies for enhancing the stability of AMPs.

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