Dimethyl fumarate as a covalent inhibitor of Cathepsin C: a novel mechanism of action explored in in-vitro and in-vivo.

Abstract

Abstract Dimethyl fumarate (DMF) is an enoate ester approved for treating autoimmune diseases like relapsing-remitting multiple sclerosis (RRMS) and psoriasis. Although its efficacy is attributed to its immunomodulatory properties but the exact mechanism of action is undeciphered. DMF tends to make Michael-adduct with cysteine residues of enzymes. The current study focuses on in-vitro experiments to find out the time-dependent enzyme inhibition of cathepsin C, which is an essential upstream target for immune cells controlling apoptosis. An in-vivo study was also performed by inducing experimental autoimmune encephalitis (EAE) on the day-1 of the experiment, and clinical scoring was done after 4 hours onwards up to day-33. Oral drug treatment was done from day-7 onwards with DMF-50 mg/kg. A significant improvement in the clinical score with DMF treatment compared to the EAE group has been observed. DMF has been shown to ameliorate demyelination in the spinal cord and reduce CD8+ and CD4+ T lymphocyte infiltration in the CNS. Moreover, a significant reduction in the cathepsin C activity and its downstream granzyme B activity in the CNS on day-33 has been noticed. The irreversible inhibition of cathepsin C indicates the efficacy of DMF on mononuclear cells.