PAD enzymes catalyse the conversion of protein-embedded arginine to citrulline. Citrullination of histones can alter gene expression through epigenetic mechanisms, and non-histone PAD targets include extracellular proteins that are citrullinated during inflammation. These modified proteins are thought to be immunogenic, particularly in RA, in which the presence of anti-citrullinated protein antibodies (ACPAs) is one of the diagnostic criteria. “If you inhibit this path you would be removing the antigen, and that should damp down the inflammation that you see in RA,” explains Paul Thompson, one of Padlock's scientific founders, who is now a professor at the University of Massachusetts Medical School, USA. He draws a parallel with coeliac disease — remove gluten, and you remove many of the symptoms.

Thompson's laboratory, then at The University of South Carolina, USA, developed the first potent and specific covalent inhibitors of PAD4 (encoded by PADI4) (Biochemistry 45, 11727–11736; 2006). These molecules had efficacy in animal models of RA, ulcerative colitis, lupus, atherosclerosis, neonatal hypoxic ischaemia and spinal cord injury.

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