New Cyclic Lipopeptide Compounds for Efficiently Inhibiting Cellular Inflammation and Collagen-Induced Arthritis in Mice

  • J Med Chem. 2025 Sep 25;68(18):19767-19780. doi: 10.1021/acs.jmedchem.5c02095.
Yanni Ma  1  2 ,  Xu Cao  1 ,  Xiaoli Jin  1 ,  Lan Huang  1 ,  Dejia Zeng  1 ,  Zijing Xia  3 ,  Yi Liu  4 ,  Shufang Liang  1
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No.17, Third Section of Renmin South Road, Chengdu 610041, China.
  • 2. Key Laboratory of Natural Products, Henan Academy of Sciences, No. 58, Hongzhuan Road, Zhengzhou 450002, China.
  • 3. Department of Rheumatology, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4. College of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, China.
PMID: 40923559 DOI: 10.1021/acs.jmedchem.5c02095
Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease, and a large number of patients do not respond well to existing treatment strategies. Our previous report has discovered that the cyclic Lipopeptide (CLP) daptomycin (DAP) has a good suppressive arthritis activity in mice. In this study, we have designed and synthesized five novel DAP-derived CLPs by structural optimization on the loop of DAP and further studied their anti-RA effects in vitro and in vivo. Especially, CLP-d2 has better anti-RA effect than DAP due to its better pharmacokinetic parameters and peptide stability. Mechanistically, CLP-d2 effectively reduces the secretion of inflammatory factors (IL-6, TNF-α, and IL-1β) and inhibits the expression of the related proteins in NF-κB and MAPK signaling pathways, thus reducing mouse joint swelling and bone erosion and retarding arthritis progression. Our findings support the potential druggability of DAP-derived CLPs for treatment of RA.

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