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Research Interests

Deciphering molecular mechanisms using biochemical, molecular and cell biology approaches

image01  Anticancer area:

Our primary interest in the anticancer area is to investigate the cellular processes of human DNA replication and repair. We study proteins that are involved in both DNA replication and Base excision repair (BER) and Nucleotide exchange repair (NER) processes. The proper functioning of proteins involved in these processes is essential for maintaining genomic integrity and any problems with their function, expression or interactions can lead to human diseases such as cancer. The importance of DNA repair proteins has been recently highlighted with the 2015 Nobel prize for Chemistry going to Paul L. Mordick, Tomas Lindahl and Aziz Sankar in the field of DNA repair.

Our lab is studying DNA replication proteins such as Polδ, PCNA, RFC, Fen1, Lig1, PARP1 and Topo1 and their interactions with other proteins. Polδ is primarily involved in the synthesis and processing of the lagging strand DNA (composed of Okazaki fragments). PCNA is a beta clamp that harbours Polδ on the DNA. RFC is a clamp loader that loads PCNA onto the DNA, while Lig1 seals the gaps between Okazaki fragments to make the continuous lagging strand DNA. The interplay among these proteins, their post-translational modifications, mutations or other factors that lead to changes in their function, expression or interaction makes for very interesting studies with implications for genomic instability and cancer

Lig1 and FEN1 have been recently described as biomarker for breast and ovarian cancers. Clinical trials for PARP1 and Topo1 inhibitors for cancer were also in the news recently. Taking cue from these, we have conducted a pharmacophore based screening for hLig1 and Fen1 inhibitors from the CDRI compound library and have found hLig1 inhibitors that can slow down the progression of breast cancer in a mouse model. Fen1 inhibitors are being currently tested for their anticancer properties. Our lab has also developed assays for Topo1 and PARP1 and inhibitors for these proteins will be screened shortly.

Figure 1. A cartoon showing DNA replication proteins involved in leading and lagging strand synthesis.

image01  Antifungal area

The primary focus in the antifungal area is to investigate the Multidrug resistance (MDR) phenomenon in the human pathogenic fungus Candida albicans. C albicans is one of the most common causes of nosocomial fungal infections worldwide and the development of drug resistance in the last two decades has caused a lot of problems in its treatment. In our lab, apart from the traditional phenotypic screening of antifungal compounds, we are also focussing on a target based approach where we have chosen a transcription factor called TAC1 for designing and developing inhibitors that can reverse the phenomenon of drug resistance in C. albicans. Preliminary results from our lab is very promising and we have observed a reversal of Fluconazole resistance in clinical isolates in the presence of TAC1 inhibitors identified from the Zinc compound library. Lead optimization for these compounds and further screening of inhibitors from the CDRI and Maybridge compound libraries is ongoing.

Figure 2. The development of azole resistance due to over-expression of MDR pumps can be restored by targeting their regulator called TAC1.