New Cyclic Lipopeptide Compounds for Efficiently Inhibiting Cellular Inflammation and Collagen-Induced Arthritis in
Yanni Ma1,2, Xu Cao1, Xiaoli Jin1
1Department 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.
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.
