| Modern drug discovery is a rigorous multi-step process starting from target identification to the synthesis of lead compounds and their pharmacological validation as drugs in model systems. Enzymes have emerged as the most attractive targets for drug intervention, given their essential catalytic roles in numerous biological pathways as well as their unique conformation which lends itself to external manipulation. Typically, this is achieved through small molecules or peptides that exploit the structural features of a substrate or cofactor or product in order to create a moiety with very high binding affinity for the enzyme. The design of such small molecules as chemical tools to perturb biological systems has offered a facile way of deconstructing the cellular roles of several enzymes and in providing a working scaffold for designing potent drugs in the future. This work describes some initial attempts to characterize an enzyme Protein Arginine Deiminase 4 or PAD4, using methods in enzymology, chemistry and biology. PAD4 is implicated in a joint disease called Rheumatoid arthritis (RA), a disease that is incurable, despite several decades of clinical efforts. Targeting RA via PAD4 would require a detailed understanding of its enzymatic properties and cellular functions, which have so far remained poorly understood. Emerging data suggests that the important role of PAD4 in RA as well as in normal physiology may be mediated, at least in part, through its role in transcriptional regulation and apoptosis. It is hoped that our studies on characterizing the various aspects of PAD4, including catalysis and regulation, would add to this knowledge and aid in the design of specific small molecule drugs for PAD4 that may find a use as anti-RA therapeutics. |
