Protein arginine deiminase 4 (PAD4) is an enzyme predominantly expressed in granulocytes. It is responsible for the catalyzation of hydrolytic deamination arginine residues into citrulline. GSK199 is a reversible PAD4 inhibitor with an IC50 value of 200 nM. It also showed inhibitory activity against PAD4 in the presence of 0.2 mM and 2 mM calcium with IC50 values of 250 nM and 1.0 µM, respectively. GSK199 dose-dependently inhibited PAD4 citrullination of benzoyl-arginine ethyl ester substrate in the presence of 0.2 mM calcium. Pretreatment of 10 µM GSK199 markedly inhibited the formation of citrullination and neutrophil extracellular trap in vitro[1]. In the murine collagen-induced arthritis (CIA) model of rheumatoid arthritis, daily subcutaneous injection of GSK199 resulted in a 25% (10 mg/kg) and 54% (30 mg/kg q.d.) reduction in clinical disease activity in comparison to saline-treated controls, and a decrease of 52% (10 mg/kg) and 71% (30 mg/kg q.d.) relative to untreated animals. Treatment with GSK199 (30 mg/kg b.i.d.) also reduced joint destruction and C3 deposition in the joints of CIA mice[2].
作用机制
GSK199 binds to PAD4 to induce a β-hairpin structure that allows the packing of hydrophobic residues Phe634 and Val643 to the center of the inhibitor. The close packing of Phe634 against GSK199 accounted for the high specificity of GSK199 for PAD4.
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