Immunomodulatory actions of lanthionine synthetase C-like 2-based drugs

Current inflammatory bowel disease (IBD) treatments are associated with significant side-effects. We identified lanthionine synthetase component C-like protein 2 (LANCL2) as a target for abscisic acid, a naturally occurring compound with potent anti- inflammatory effects. The goal of this study was to determine the role of LANCL2 as a therapeutic target for developing novel anti-inflammatory drugs. Structure-based virtual screening was performed using a compound library from National Cancer Institute Diversity Set II. To validate the anti-inflammatory efficacy of the top-ranking compound 61610, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate-induced colitis. Our findings showed that oral administration of 61610 (20 mg/kg/day) ameliorated experimental colitis by down- modulating colonic inflammatory gene expression and favoring regulatory T cell responses. We also investigated the cell specificity and molecular targets underlying the anti-inflammatory mechanism of 61610. Our in vivo findings indicate that anti- inflammatory efficacy of 61610 depends on macrophage expression of peroxisome proliferator-activated receptor γ, a receptor downstream of LANCL2. In summary, we used an integrated drug discovery platform consisting of molecular modeling approaches followed by experimental validation to confirm LANCL2 as a novel therapeutic target against IBD and demonstrated that 61610 is a novel anti- inflammatory drug.