Sanjukta Mukherjee is an independent fellow in our group funded by the NCBS campus fellowship program. She trained in chemical biology and molecular biology. She obtained her PhD on 2012 from CSIR-Indian Institute of Chemical Biology (IICB), Kolkata. Then she joined Institute of Scientific and Industrial Research (ISIR), Osaka University on 2013 as post-doctoral fellow and subsequently, after two and half years promoted as an assistant professor. At 2017, she relocated back to India and joined NCBS. She also received one Indo-Japan grant for joint research under India-Japan Cooperative Science Programme (IJCSP2017). Currently, she also associated with Osaka university as specially appointed assistant professor (Visiting) under Osaka University’s International Joint Research Promotion Program. Her research interests lie in the interdisciplinary fields of chemical biology, biophysics and molecular biology. At fundamental level her research involves design and development of small molecular chemical probe to recognize nucleic acids by sequence and structure specific manner, followed by exploratory studies on the interplay between nucleic acid-small molecule interaction at molecular level as modulator of DNA/RNA structure and function in genetic disorders. Further, bring in-depth molecular insight into its regulatory role for the targeted disease pathogenesis using in vitro and in vivo models. Ultimately extend this work from basic to translational to develop DNA/RNA targeted chemical probe and/or therapeutics for genetic disorder. She is also interested to develop different strategies to identify binding DNA/RNA for a small molecule of interest.
msanjukta at ncbs dot res dot in
Probing DNA/RNA structure by small molecule in genetic disorders
Gene mutation or mutagenesis is one causative that can affect anywhere from a single DNA building block to a large segment of a chromosome that includes many genes. A mutated gene transcribed into precursor mRNA (pre-mRNA) creating an error in the instruction needed to produce certain protein. It subsequently translates into a malfunctional version of the protein and leads to pathogenesis of genetic disorder. On the other hand recent exploration of RNA biology reveals regulatory role of both coding RNA (mRNA) and non-coding RNA (ncRNA) in human disease and created a paradigm shift in the chemical probing and drug discovery, which is firmly protein centric. It has also expanded the potential pool of drug targets to enable precision medicine for the future. However, so far, most of the RNA binding molecules are discovered either by phenotype screening or by screening of compound library against therapeutically well-validated RNA targets. These modes of screening do not take into consideration the target complexity and selectivity. It is also unable to provide a clear insight on mode of molecular interactions. Alternatively, despite the enormous potential of rational designing approach, presently, it is only in its infancy. To address this problem, my work involves development of novel class of small molecular chemical probe using a rational design approach. One such class of molecule recently developed is the cyclic mismatch binding ligands (CMBLs), aiming to target specific sequence/structure of nucleic acids (DNA and/or RNA).
(a) Development of different strategies to identify binding DNA/RNA sequence for small molecule: We have developed a SELEX based in vitro selection procedure and an SPR based screening strategy to identify the binding nucleic acid sequence for small molecule using recently developed novel CMBL analogues. Where we identified the binding hairpin loop motif of pre-miRNA for a CMBL analogue. We are also using a SPR based screening strategies to identify binding of small molecule to nucleic acids (work done in collaboration with Osaka University). Current interest at NCBS is development of in vitro strategies to identify binding nucleic acid sequence in cellular system.
(b) Regulation of miRNA by small molecule in cancer targeting its biogenesis: Human genome ENCODE project revealed more than 70% of the human genome was transcribed into RNAs and only 3% of it was translated into proteins. These large fraction of non-coding RNAs (ncRNAs) that does not code for any protein have important implications in gene regulation, cellular functions and diseases pathogenesis such as micro-RNA (miRNA), ribosomal-RNA (r-RNA), transfer-RNA (t-RNA) and more recently long non-coding RNA (lncRNA). My current focus is on miRNA (specifically oncomiR) in cancer. MiR24 is observed to act as an oncomiR in cervical cancer and is one of the overexpressed miRNAs in metastatic cervical cancer cell line (CaSki). Pre-miR24-2 comprises characteristic hairpin loop motif for CMBL binding. Currently we are trying to understand the CMBL mediated regulation of miR24 targeting its precursor (pre-miR-24-2) and its regulatory effect on cancer phenotypes. Bhagyashree Shealer (JRF) is currently associated with this project. Shefta E Moula (JRF) is also associated with this project for PK/PD study of CMBL. She is also evaluating the anti-cancer activity of CMBL using in vivo mice model.
(c) Exploring interaction of small molecule (CMBL) and telomeric G-quadruplex DNA: Telomere DNA length and telomerase activity plays a crucial role for cancer initiation and for the survival of tumors. It is also a well validated target for the development of anticancer drugs. Diverse approaches have been adopted to achieve this goal. The most advanced area of small-molecule drug discovery involves identification or development of G-quadruplex-telomere DNA stabilizing ligands. SPR-based screening of CMBLs revealed binding affinity of few CMBL analogues towards telomere DNA repeat. In another study we are exploring the regulatory effect of potential CMBL binders on conformational switching of telomere DNA structure, telomere length and cancer phenotypes. Swati Chowdhury (Intern) currently involve in this project.
(d) Development of DNA/RNA targeted novel fluorescence probe: Long wavelength probes would enable comprehensive imaging to reduce imaging noise and allow deep tissue imaging. Towards this goal in another project we are developing novel CMBL analogues incorporating chromophore that has emission maxima at longer wavelength and exploring its potential as DNA/RNA targeted fluorescence probe. Dr. Siddan Gouthaman (Research Assistant) is working in this project.
(e) Exploring probe application of CMBL in neuromodulation of expanded repeat disorders: In parallel, my another research focus is to probe application of CMBLs in neuromodulation of expanded repeat disorders, where present targets are expanded CAG and CGG repeats, cause of polyglutamine (polyQ) disorders and Fragile X-associated tremor/ataxia syndrome (FXTAS) respectively. Study on FXTAS is going on collaborating with Osaka University and Adam Mickiewicz University, Poland. Study on polyglutamine (polyQ) disorders is going on collaborating with Osaka University and partly at NCBS.
Apart from it I am also guiding Nayim Paul (TWAS PhD fellow in our group) for his doctorate thesis, where he is exploring anti-cancer activity of natural product extract.
“Indo-Japan (NCBS/inStem-ISIR, Osaka University) Meeting: Interfacing Chemistry and Biology” on 11th-12th March 2019 at Malgova, NCBS, Bangalore (https://www.ncbs.res.in/events/indo-japan).
“2nd Indo-Japan (NCBS/inStem-ISIR, Osaka University) Meeting: Interfacing Chemistry and Biology” on 17th February 2020 at Malgova, NCBS, Bangalore (https://www.ncbs.res.in/events/ncbs-indo-japan).
1. Sanjukta Mukherjee, Leszek Błaszczyk, Wojciech Rypniewski, Christoph Falschlunger, Ronald Micura, Asako Murata, Chikara Dohno, Kazuhiko Nakatani, and Agnieszka Kiliszek; “Structural insights into synthetic ligands targeting A–A pairs in disease-related CAG RNA repeats” Nucleic Acids Research. 2019, 47, 10906-10913 (Impact factor: 11.147).
2. Takahito Ohshiro, Rajiv Kumar Verma, Kazumichi Yokota, Makusu Tsutsui, Sanjukta Mukherjee, Tomoji Kawai, Kazuhiko Nakatani, and Masateru Taniguch; “Electrical nucleotide sensor based on synthetic guanine-receptor-modified electrodes” ChemistrySelect 2018, 3, 3819-3824 (Impact factor: 1.716).
3. Patryk Konieczny, Sanjukta Mukherjee, Chikara Dohno, Kazuhiko Nakatani, Krzysztof Sobczak; “Cyclic naphthyridine dimers as therapeutic agents for fragile X-associated tremor/ataxia syndrome” Acta Neurobiologiae Experimentalis 2017, 77 (Suppl. 1), P.72 (Impact factor: 1.529).
4. Kazuhiko Nakatani, Nozomi Natsuhara, Yuki Mori, Sanjukta Mukherjee, Bimolendu Das, Asako Murata; “Synthesis of naphthyridine dimers with conformational restriction and the binding to DNA and RNA” Chem. Asian J. 2017, 12, 3077-3087 (Impact factor: 3.698)
5. Sanjukta Mukherjee,* Chikara Dohno, Kazuhiko Nakatani*; “Design and Synthesis of Cyclic Mismatch-Binding Ligands (CMBLs) with Variable Linkers by Ring-Closing Metathesis and their Photophysical and DNA Repeat Binding Properties” Chem. Eur. J. 2017, 23, 11385-11396 (Impact factor: 5.16)
6. Sanjukta Mukherjee, Chikara Dohno, Kaori Asano, Kazuhiko Nakatani; “Cyclic mismatch binding ligand CMBL4 binds to the 5’-T-3’/5’-GG-3’ site by inducing the flipping out of thymine base” Nucleic Acids Research. 2016, 44, 7090–7099 (Impact factor: 11.147)
7. Biswajit Chakraborty, Debasmita Dutta, Sanjukta Mukherjee, Supriya Das, Nakul C. Maiti, Padma Das, Chinmay Chowdhury; “Synthesis and biological evolution of a novel betulinic acid derivative as an inducer of apoptosis in human colon carcinoma cells (HT-29)”. Eur. J. Med Chem. 2015, 102, 93-105 (Impact factor: 4.833)
8. Chinmay Chowdhury, Sanjukta Mukherjee, Bimolendu Das and Basudeb Achari; “Palladium catalysed approach for the general synthesis of (E)-(2-Arylmethylidene-N-tosylindolines and (E)-2-Arylmethylidene-N-tosyl/nosyltetrahydroquinolines: Access to 2-substituted indoles and quinolines” J. Org. Chem. 2012, 77, 5108-5119 (Impact factor: 4.745)
9. Chinmay Chowdhury, Sanjukta Mukherjee, Biswajit Chakraborty, Basudeb Achari; “A Rapid and Facile Method for the General synthesis of 3-Aryl Substituted 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their Ring Fused Analogues” Org. Biomol. Chem. 2011, 9, 5856-5862 (Impact factor: 3.490)
10. Chinmay Chowdhury, Kaushik Brahma, Sanjukta Mukherjee and Anup Kumar Sasmal; “Totally Regio- and Stereoselective Synthesis of (E)-3-Arylidene-3,4-dihydro-2H-1,4-benzoxazines under Palladium Catalyst” Tetrahedron Lett. 2010, 51, 2859-2861 (Impact factor: 2.259)
11. Chinmay Chowdhury, Sanjukta Mukherjee, Bimolendu Das and Basudeb Achari; “Expedient and Rapid Synthesis of 1,2,3-Triazolo[5,1-c]morpholines through Palladium-Copper Catalysis” J. Org. Chem. 2009, 74, 3612-3615 (Impact factor: 4.745)