BB-Cl-Amidine

Protein arginine deiminase 4 (PAD4) catalyzes the post-translational modification of arginine residues on histones to form citrulline, which can alter gene expression. Dysregulated PAD4 activity has been implicated in cancer and rheumatoid arthritis. Cl-amidine is an inhibitor of PAD4 deimination activity with an IC50 value of 5.9 µM in an in vitro activity assay. BB-Cl-Amidine is a Cl-amidine derivative that retains functional components but possesses a C-terminal benzimidazole designed to limit proteolysis of the C-terminal amide. The cellular potency of BB-Cl-amidine against PAD4 activity is increased 20-fold over the parent compound (EC50 = 8.8 µM, vs. >200 µM for Cl-amidine). BB-Cl-Amidine also has a significantly longer in vivo half-life than Cl-amidine (1.75 h vs. ~15 min, respectively). Both compounds inhibit the formation of neutrophil extracellular traps without altering H2O2 production by neutrophils. BB-Cl-Amidine is effective in vivo, improving endothelial function while downregulating the expression of type I interferon-regulated genes in MRL/lpr mice.