TIFR
Department of Chemical Sciences
School of Natural Sciences

November 9, 2020 at 4.30 pm (via Zoom)

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, their metabolites and halogenated nucleosides as well as 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 deiodination 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. We developed nahthyl-based organo-sulphur and/or selenium compounds as functional mimics of DIO3, and showed that deiodination of thyroid hormones and various metabolites by these compounds relies on the synergistic actions of halogen and chalcogen bonding interactions. These nahthyl-based organochalcogen compounds were also used to dehalogenate the halogenated nucleosides that can be incorporated into DNA during DNA replication and cause potential DNA damages in the presence of UV irradiation. Additionally, we discovered that commercial T4, a generic drug prescribed for hypothyroidism, exists in at least two different stable crystalline modifications with different three-dimensional structure, conformation, physical properties and solubility.

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 several PAD inhibitors are known in the literature. To reduce the off-target toxicity, we developed an azobenzene-substituted PAD2 inhibitor that undergoes trans-cis photoisomerism and can be activated at the target cell/tissue with light. Notably, the cis-isomer of this inhibitor is 10-fold more active than its trans-isomer. Furthermore, 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. Detailed studies indicate that the potency and isozyme-selectivity of this inhibitor is due to the formation of a halogen bond between the inhibitor and PAD1 active site. This inhibitor exhibited excellent efficacy for the inhibition of histone H3 citrullination 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, D. Manna, G. Mugesh, Angew. Chem. Int. Ed. 2015, 54, 9298.

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

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

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.

 

7. S. Mondal, S. S. Parelkar, M. Nagar, P. R. Thompson, ACS Chem. Biol. 2018, 13, 1057.

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