TIFR
Department of Chemical Sciences
School of Natural Sciences

March 23, 2020 at 4.00 pm in AG-69

Title :

From Designing Enzyme Mimetics to Probing Protein Citrullination

Abstract :

In this seminar, I’ll discuss my doctoral research on the biomimetic dehalogenation of thyroid hormones (THs), their metabolites and halogenated nucleosides as well as part of my postdoctoral research on the development of small molecule inhibitors and chemical probes of protein arginine deiminases (PADs) that catalyze protein citrullination.

     Thyroid gland produces thyroxine (T4) as a prohormone and regioselective deiodinations by a group of mammalian selenoenzymes, iodothyronine deiodinase type 1 (DIO1), type 2 (DIO2) and type 3 (DIO3) play important roles in the activation and inactivation of T4. Naphthyl-based organo- sulphur and/or selenium compounds are developed as functionally mimics of DIO3. The kinetics and regioselectivity of biomimetic deiodinations of THs and their metabolites are explained on the basis of S/Se∙∙∙I halogen bonding and S/Se∙∙∙S/Se chalcogen bonding. These organochalcogen compounds also mediate the dehalogenation of halogenated nucleosides that are incorporated into DNA during DNA replication and cause potential DNA damages in the presence of UV irradiation. In addition to these, I’ll also discuss the polymorphism of commercial thyroxine, a life-saver of millions of people suffering from hypothyroidism, and its implications on the bioavailability of the drug.

     Citrullination is a post-translational modification of arginine, catalyzed by a group of hydrolases called protein arginine deiminases (PADs – PAD1, 2, 3 and 4). Despite various physiological roles, protein hypercitrullination is associated with various diseases including rheumatoid arthritis (RA), lupus, ulcerative colitis (UC), multiple sclerosis (MS) and certain cancers. These strong disease links have established PADs as potential therapeutic targets and numerous PAD inhibitors are known in the literature. Using a fluoroacetamidine warhead and iodo-substitutions in the molecular scaffold, we developed the first potent PAD1 inhibitor with 74-fold selectivity over other PADs. Structure-activity relationship studies indicate that the potency and isozyme-selectivity of this inhibitor is due to the formation of a halogen bond between the iodine atoms and PAD1 active site. This inhibitor exhibits excellent efficiency for the inhibition of PAD1 in HEK293TPAD1 cells and mouse zygotes. Based on this molecular scaffold, we also developed a PAD1-selective activity-based probe with remarkable cellular efficacy and proteome selectivity.

References:

1. S. Mondal, K. Raja, U. Schweizer, G. Mugesh, Angew. Chem. Int. Ed. 2016, 55, 7606.

2. S. Mondal, G. Mugesh, Chem. Eur. J. 2014, 20, 11120.

3. S. Mondal, D. Manna, G. Mugesh, Angew. Chem. Int. Ed. 2015, 54, 9298.

4. S. Mondal, G. Mugesh, Angew. Chem. Int. Ed. 2015, 54, 10833.

5. S. Mondal, G. Mugesh, Chem. Eur. J., 2019, 25, 1773.

5. S. Mondal, P. R. Thompson, Acc. Chem. Res. 2019, 52, 818.

6. S. Mondal, X. Gong, X. Zhang, A. J. Salinger, L. Zheng, S. Sen, E. Weerapana, X. Zhang,

    P. R. Thompson, Angew. Chem. Int. Ed. 2019, 58, 12476.