Structural Modification and Anti-inflammatory Evaluation of Deep-Sea-Derived Cycloheptapeptide Derivatives against Inflammatory Bowel Disease via NLRP3 Inflammasome Signaling Suppression

The NLRP3 inflammasome plays a central role in the innate immune response of inflammatory bowel disease (IBD), and its excessive activation drives the release of pro-inflammatory cytokines and compromises intestinal mucosal barrier integrity. In this study, the natural cycloheptapeptide unguisin E (1) was identified through anti-inflammatory screening of a marine-derived molecule library. To improve its anti-inflammatory potency, 1 was employed as a lead compound for structural modification at the C-2 position of the indole moiety via Suzuki coupling, affording a series of cycloheptapeptide derivatives (2−40). Among them, CHNQD-01024 (12) significantly inhibited IL-1β release from the NLRP3 inflammasome in THP-1 and J774A.1 cell lines at 0.4 μM, exhibiting inhibition potency comparable to the positive control MCC950 at 2 μM. In the DSS-induced colitis mouse model, CHNQD-01024 significantly ameliorated systemic inflammation, mitigated colonic tissue damage, and restored intestinal barrier function at doses of 5−15 mg/kg, with efficacy comparable to the first-line clinical drug 5-ASA at 50 mg/kg. Mechanistic studies showed that CHNQD-01024 suppressed NLRP3 inflammasome-associated inflammatory signaling, accompanied by the inhibition of NF-κB signaling and ROS production, reduced NLRP3 expression, and impaired ASC oligomerization. Taken together, these findings identify CHNQD-01024 as a promising marine fungal-derived anti-inflammatory lead suppressing NLRP3 inflammasome-associated signaling.