Evaluation of the immunomodulatory effects of novel phosphinic acid derivatives in vitro and in a murine colitis model

T cells and cytokines are key contributors to the pathogenesis of inflammatory bowel disease (IBD), where dysregulated immune activation drives chronic intestinal inflammation. Phosphinic acid compounds are biologically active molecules that function as enzyme inhibitors and have been investigated for diverse pharmacological applications, including their potential therapeutics in inflammatory diseases. In this study, we investigated the immunomodulatory effects of seven novel phosphinic acid derivatives, including PAC-tryptophan (PAC-Trp), PAC-leucine (PAC-Leu), PAC-proline (PAC-Pro), PAC-phenylalanine (PAC-Phe), PAC-alanine (PAC-Ala), PAC-valine (PAC-Val), and PAC-glycine (PAC-Gly), using in vitro T-cell assays. Four derivatives (PAC-Trp, PAC-Phe, PAC-Ala, and PAC-Gly) suppressed T cell proliferation without affecting cell viability, suggesting immunosuppressive potentials. Additionally, PAC-Gly showed a tendency to reduce IFN-γ-secreting T cells, although the difference was not statistically significant. We then evaluated the therapeutic effect of PAC-Gly in the dextran sulfate sodium (DSS)-induced colitis mouse model. PAC-Gly conferred no therapeutic benefit, as evidenced by its inability to attenuate body weight loss, reduce disease activity index (DAI) scores, prevent colon shortening, or alleviate histopathological damage. Furthermore, PAC-Gly significantly increased colonic mRNA expression of IL-6, TNF-α, and IL-4 cytokines compared with the control group. While in vitro studies showed that some PACs can inhibit T cell proliferation, investigations of their immunomodulatory effects in the DSS-induced colitis mouse model did not disclose any clinical benefits.