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

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.