Indian Institute of Technology Bombay, Mumbai, India
Tata Institute of Fundamental Research, Centre for Interdisciplinary Sciences, Hyderabad, India
My journey into research
As I reminisce about my student days, my thoughts go back to a moment in an advanced asymmetric organic synthesis course that I took as a part of master’s degree program. Our teacher was explaining the implications of stereochemistry on human health. He mentioned – “the ‘chirality’ is a very delicate molecular property, where one enantiomer of a chiral molecule could be a life saving medicine but the other one could be a poison to human health. For instance, one enantiomer of ‘Naproxen’ is used for the treatment of severe arthritic pain, whereas the other enantiomer causes liver poisoning with no analgesic effect. Therefore, when performing asymmetric synthesis, the presence of the undesired isomer, even if it is innocent, should, whenever possible, be avoided.” I was amazed, and quite astonished to know the reason behind it. Nature has created such a sophisticated living organism where most of the biomolecules are inherently chiral and their interactions are highly stereospecific, leading to profound differences in activity of different isomers of the same compound. At that young age, I was thrilled to know that all proteins in a living organism are made up of L-amino acids, whereas all sugars are of D-chirality. At the same time, I was also loaded with a bundle of unanswered questions. Why nature has chosen L-proteins and D-sugars, but not the other way around? Are there any other living organisms in distant worlds, where all proteins are made up of D-amino acids and the sugars are of L-chirality? Is the D-protein world accessible, at least by synthetic chemistry? Seven years later, partly by co-incidence and partly by my inherent silent desire, in my post-doc, I was fortunate to work on many research projects where I had to chemically synthesize proteins that are made up of all D-amino acids.
My career in research started in the year 1999 at the Department of Organic Chemistry, Indian Institute of Science, Bangalore with Professor Uday Maitra, just after completing my master’s degree in chemistry from Visva-Bharati University, Santiniketan. This was my first experience in a drug discovery research program, in collaboration with a California based biotechnology company, MitoKor. I worked as a part of a small team of talented young scientists on the design and chemical syntheses of library of small organic molecules. The goal was to identify lead molecules, which would be effective against neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. It was a great learning curve for me where I got hands-on experience in organic synthesis, and it was immensely gratifying to apply my classroom knowledge of chemical reactions for practical applications. This work inspired me to continue to pursue a career in research. After a one-year stay at the Indian Institute of Science, Bangalore, I started exploring research areas for pursuing my Ph.D. degree. I was quite impressed by the work of Professor Sambasivarao Kotha from Indian Institute of Technology Bombay, who was developing methodologies for the synthesis of a wide range of very unusual α-amino acid derivatives. Realizing that it would be a great opportunity for me to gain some experience in synthesizing unnatural amino acids and incorporating them into biologically active peptides, I joined in a PhD program at the Indian Institute of Technology, Bombay. There, in one of my research projects, I had to make a conformationally constrained dicarba analogue of cystine. I decided to prepare a C60 fullerene (Bucky Ball) based analogue of cystine where the disulfide bond would be replaced by a carbon cluster, a fullerene (C60) molecule. At that time, when searching literatures to know more about fullerene, I came across a landmark paper by Friedman et al. who showed, by computer simulation, that being in the similar diameter range the C60 molecule would snugly fit into the hydrophobic cleft of an HIV-protease enzyme. Being aware of this fact, I came up with a naïve idea of incorporating my fullerene-based unnatural amino acid into a peptide that would be recognized by HIV protease, and the HIV-protease hydrophobic cleft would then immediately be blocked by the fullerene moiety. It was then that I came across a research article by Professor Stephen B. H. Kent, published years ago in ‘Science’. In that seminal contribution Professor Kent reported the chemical synthesis of not only the native HIV-protease, but also the mirror image form of the HIV protease molecule that exhibited reciprocal chiral specificity with mirror image protease inhibitors. I was simply spellbound by Professor Kent’s work. Consequently, I became determined to work with him for my postdoctoral studies and to learn how to make proteins using chemistry.
Over the past few years, I have had the great privilege to work with Professor Stephen B. H. Kent, first as a postdoctoral scholar, and more recently as a research professional, at the University of Chicago. During my post-doctoral training, in the Kent lab, I made, by total chemical synthesis, a series of native proteins and their enantiomers (made up entirely of D-amino acids and glycine), and applied these mirror image protein molecules to understand the molecular basis of protein function. After a successful post-doctoral experience, I decided to stay in the same lab as a Research Professional (Research Faculty position) and accepted an offer to work on a very challenging project to develop a novel D-protein antagonist of vascular endothelial growth factor (VEGF-A) function using a unique combination of chemistry and biology. I was brave enough to accept such a challenging project and ultimately, very successfully, achieved my goal. We systematically identified a D-protein antagonist of VEGF-A function and determined the first ever crystal structure of a new class of protein-protein complex, consisting of two non-identical interacting protein molecules of opposite chirality, by racemic protein crystallography. This work categorically illustrated the potential of D-proteins as a novel class of molecules for antagonizing the action of natural proteins.
Here I am today, equipped with all the necessary skill sets, together with a creative outlook, ready to venture into a challenging and new research problem in an academic institute in my native India. Being a chemist, I now have the access to the new world of protein molecules – the mirror image proteins. In my future research endeavors, I will combine my synthetic organic chemistry and chemical protein synthesis skill sets for the design and synthesis of novel polypeptide chain topology; fabrication of unique protein analogues that include the chemical modification of the polypeptide backbone of a protein molecule, and the incorporation of fixed elements of secondary structure, all aiming towards novel protein drug design. To start with, I have designed a research project on the development of D-protein candidate therapeutics against malaria. Many of my colleagues ask me – why malaria and why now, when there already artimisinin exists as an antimalarial drug? I tell them – although artimisinin is there, artimisinin-resistant strains are also there, and a growing number of artimisinin-resistant new strains have recently started immerging as well. If we do not get ourselves ready with an alternative approach to eliminate malaria from our planet, “we’ll be back where we were before World War II”.
I am deeply honored to be one of the recipients of the intermediate fellowship award and am grateful to the Wellcome Trust/DBT India Alliance for providing me with the initial grant support to carry out my proposed research in India. I am very confident that my diverse expertise at the interface of chemistry and biology and my passion for innovation will make me a very successful scientist that I always envisioned being.