Efficient synthesis, stability-guided optimization and anti-ulcerative colitis evaluation of bee venom peptide melittin.

Ulcerative colitis (UC) is considered as one of the most prevalent inflammatory bowel diseases (IBDs), which increases risks for colectomy and colorectal cancer. However, due to moderate efficiency and potential side effects of first-line drugs, it is desirable to develop more efficient anti-UC agents. The natural peptide Melittin, which is the main active ingredient of bee venom, is considered as a potential scaffold for the development of anti-UC drugs. Nevertheless, as a linear amphipathic peptide, Melittin could be degraded by various proteases, suffering from poor stability and short half-lives. Previous studies on structural optimization or the potential of Melittin-derived peptides for anti-UC applications still remain limited. In this study, the stability-guided optimization and anti-UC evaluation were conducted on Melittin. The robust synthetic strategy, in vivo anti-UC activity, and anti-inflammatory mechanism were investigated. Compared with Melittin, the derived peptides represented by PCJ-675 were found to exhibit improved proteolytic stability. In the dextran sulfate sodium (DSS)-induced UC mice model, PCJ-675 could significantly alleviate both colon shortening and suppress inflammation symptoms in colon tissue. The western blotting and biochemical indicators suggested that the oral administration of PCJ-675 could protect the colon in colitis mice by inhibiting both the excessive activation of the inflammation-related TLR4/NF-κB pathway and the overexpression of pro-inflammatory cytokines (eg, IL-1β, IL-6, and TNF-α). Collectively, this study not only stablished robust strategies to improve the stability and anti-UC potential of Melittin, but also provided valuable references for the future development of natural cytotoxic peptides based anti-UC agents.