PAD4 (peptidylarginine deiminase 4)

Class

PAD4 inhibitor (originated from Padlock Therapeutics, acquired by BMS in 2016)

Pathway

Blocks PAD4-mediated protein citrullination implicated in RA autoantibody (ACPA) production

PAD4 is an enzyme, peptidylarginine deiminase 4, that catalyzes citrullination—the conversion of arginine residues in proteins to citrulline. This post-translational modification alters protein structure and function and can render self-proteins immunogenic. In rheumatoid arthritis (RA), citrullinated proteins are recognized by the immune system, driving production of anti-citrullinated protein antibodies (ACPAs), a hallmark of the disease's autoimmune process. PAD4 is also central to NETosis, a form of neutrophil cell death that releases neutrophil extracellular traps (NETs) laden with citrullinated histones and other antigens, further amplifying autoantibody generation and inflammation. By inhibiting PAD4 catalytic activity, it may be possible to reduce the pool of citrullinated autoantigens, dampen ACPA formation, and limit downstream inflammatory signaling that perpetuates joint damage in RA. This mechanism is of interest not only in RA but potentially in other conditions where citrullination and NET formation contribute to pathology, such as certain vasculitides and inflammatory disorders. Because citrullination normally participates in various physiological processes, including gene regulation and innate immune defense, achieving disease-modifying inhibition while preserving normal PAD4 functions elsewhere is a central consideration in developing this class of agents.