Protein-arginine deiminase (PAD) (PAD)

Protein-arginine deiminase (PAD) is a family of calcium-dependent enzymes, including five human isoforms (PAD1, PAD2, PAD3, PAD4, and PAD6), that catalyze the post-translational conversion of peptidyl-arginine residues into peptidyl-citrulline [1, 3, 16]. This process, termed citrullination or deimination, significantly alters a protein's chemical properties and structural conformation, playing essential roles in physiological processes such as skin cornification, epigenetic gene regulation via histone modification, and the formation of neutrophil extracellular traps (NETs) as part of the innate immune response [1, 12, 18]. Dysregulation or hyperactivation of these enzymes, particularly PAD2 and PAD4, is strongly linked to the pathogenesis of several autoimmune and inflammatory diseases, most notably rheumatoid arthritis (RA), where citrullinated proteins serve as neoantigens that trigger the production of anti-citrullinated protein antibodies (ACPAs) [2, 10, 12].\n\nIn the therapeutic landscape, PADs are prominent drug targets for autoimmune disorders, oncology, and neurodegenerative diseases [1, 13, 17]. Small-molecule inhibitors, including pan-PAD inhibitors like Cl-amidine and isoform-selective agents such as JNJ-64619178 or GSK199, are designed to suppress the production of pathogenic citrullinated antigens and inhibit excessive NETosis [8, 10, 14]. While targeting PADs offers a novel approach to managing chronic inflammation and potentially sensitizing cancer cells to therapy, pharmacological intervention faces challenges regarding isoform selectivity and the potential for impaired host defense due to the inhibition of NET-mediated immunity [1, 8, 15].

Other names

Peptidylarginine deiminasePeptidyl-arginine deiminasePADIProtein-L-arginine iminohydrolase

Inhibition of the hydrolytic deimination of peptidyl-arginine to peptidyl-citrulline, preventing the formation of citrullinated neoantigens and inhibiting NETosis.