Functional model of metalloenzymes

Metalloenzymes are enzymes that contain metal ions at their active sites, which play a crucial role in catalyzing various chemical reactions in living organisms. These metal ions impart unique reactivity, selectivity, and efficiency to the enzymes, making them fascinating targets for biomimetic research. We aim to construct synthetic metalloenzymes by incorporating metal ions into synthetic biomimetic scaffolds or artificial protein frameworks. These synthetic constructs can mimic the reactivity and selectivity of natural metalloenzymes while offering the potential for fine-tuning and customization of their reactivity and selectivity. Currently, we are developing a chemical model for an enzyme called TET, ten-eleven translocation enzyme.  This enzyme is responsible for oxidizing the methyl group of the methylated cytosine (mC) residue in DNA. The TET enzyme is a Fe-containing enzyme, and the Fe centre is coordinated to two histidine residues, one glutamate residue and an alpha-ketoglutarate cofactor. The TET enzyme iteratively oxidizes the methyl group in cytosine residue to hydroxy (5-hmC), formyl (5-fC), and carboxy (5-caC), respectively. This stepwise activation of strong C-H bond at ambient conditions is not straightforward. Also, the distribution of oxidized 5-mC derivatives are not uniform, meaning the TET enzyme has different substrate selectivity. We are trying to understand all these unsolved mistry of the TET enzyme by designing small molecule-based synthetic models.    

Controlling metal homeostasis 

The concentration of each and every essential elements in the biological system are tightly regulated. Metals, especially transition metals are not an exception in this regard. Metal ions play vital roles in numerous biological processes, ranging from enzymatic catalysis and electron transfer to DNA repair and gene regulation. Maintaining the proper balance of metal ions within cells is essential for their optimal functioning, and disruptions in metal homeostasis have been linked to various disease states. Our group aims to develop small molecules that can interact with specific metal ions in biological systems. By selectively binding to these metal ions, these molecules can modulate their concentration, distribution, and reactivity, allowing precise control over metal homeostasis. 

Bioinspired catalysis

As the demand for efficient and cost-effective catalysts continues to grow across various fields of synthetic and applied chemistry, nature offers a wealth of information through its diverse biological systems, showcasing enzymes with unparalleled catalytic efficiency and selectivity. Enzymes catalyze cellular reactions with remarkable chemo, regio, and stereoselectivity, surpassing the capabilities of modern chemical synthesis laboratories. However, utilizing natural enzymes as catalysts in synthetic laboratories presents challenges due to their complexity, large size, cost, and stability under non-physiological conditions. In our laboratory, we aim to leverage the extensive molecular-level knowledge of these biocatalysts to design and synthesize simpler counterparts that retain similar or identical functions. By harnessing the advantages of natural enzymes while addressing their limitations, we strive to develop more accessible and practical catalysts for diverse chemical synthesis applications 

Photopharmacology

We are trying to harness the power of light and small molecules to precisely manipulate and regulate various biological processes. Our research focuses on developing innovative strategies that combine light-responsive small molecules with biological systems, enabling unprecedented control over cellular functions with spatial and temporal precision. By leveraging the power of light and small molecules, we seek to provide researchers and clinicians with unprecedented control and manipulation capabilities, opening new frontiers in biology, medicine, and biotechnology. 

Targeted protein degradation

Targeted protein degradation represents a promising strategy for modulating protein function by selectively removing specific proteins from the cellular environment. This approach offers distinct advantages over traditional inhibition or activation methods, as it allows for the elimination of disease-causing proteins, oncoproteins, or unwanted cellular components.

At our research center, we focus on developing small molecules known as proteolysis-targeting chimeras (PROTACs) that harness the cell's natural protein degradation machinery. PROTACs consist of two key components: a ligand that binds to the target protein of interest and a ligand that recruits an E3 ubiquitin ligase, leading to the tagging of the target protein with ubiquitin. This ubiquitinated protein is then recognized and degraded by the cellular proteasome. By selectively degrading disease-causing proteins or undesirable cellular components, we aim to develop innovative treatments for cancer, neurodegenerative disorders, and other challenging diseases. 

PROTACs are useful for degrading intracellular proteins only. Whereas the LYTACs, Lysosome-targeting chimaeras, can degrade membrane-bound proteins and extracellular proteins. We are also developing small molecule-based LYTACs for extracellular protein degradation.