VIROLOGY | CANCER BIOLOGY | CHROMATIN REMODELLING
SARS-CoV-2
SARS-CoV2 has taken a toll over the world by hijacking the human health. As of January 2023, about 600 million people stand infected by the virus due to an unprecedented rate of transmission and about 6 million have lost their lives because of the disease. There are no specific therapeutics available against the virus, instead some of the antivirals have been repurposed including FDA approved drug molecules. Major drugs that have been reported are mainly against RNA dependent RNA polymerase and Main protease. Owing to the increasing rate of mutations of the virus, there is a dire need of novel therapeutics targeting some of the conserved proteins of the virus inclusive of proteases, helicases, endonucleases and polymerases. We are very hopeful that rigorous efforts from the team will contribute to the assemble of therapeutics for SARS-CoV-2 interfering with replication and infection. Recently, our team has screened wide variety of drugs indicated in different infectious diseases such as retroviral HIV infections, bacterial infections, etc. and have used biochemical and biophysical analysis to compare drugs in terms of activity on the main protease of SARS-CoV-2 . We have found that under similar laboratory conditions, Teicoplanin was found to be a much stronger inhibitor of 3CLPro. We are deciphering protein-drug interactions for the mechanism of inhibition at the molecular level. Our team is also aiming at deciphering the structural determination of various proteins for mechanistic insights of viral pathogenesis which may help to combat any future pandemics to come.
DENGUE & CHIKUNGUNYA
Dengue and Chikungunya are a mosquito-borne viral infection regarded as a potential worldwide public health problem. Infection is transmitted in humans by infected female Aedes mosquito that causes acute dengue fever to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Chikungunya virus (CHIKV) is an important recently reemerged human pathogen causing acute illness associated with fever, skin rash and arthralgia. Control of the infection through vector eradication programme, has met limited success and hence in the current scenario, a prophylactic vaccine or antiviral is so far not available to the mass. And their development requires more detailed understanding of the mechanism and factors affecting virus replication/progression in an infected cell. Recently, our lab has screened and evaluated medicinal herbs as well as approved molecules repurposing against Chikungunya virus and found significant leads which may help in finding potential interceptors agains Chikungunya.
DENV has a long open reading frame (ORF) of 11kb (appx.) flanked by untranslated regions (UTRs) at the 5’ and 3’ end which contains unique structural and functional elements required for viral pathogenesis. The ORF is translated into a polyprotein that is processed by cellular and viral proteases to yield structural proteins and nonstructural proteins. Following attachment and entry, a number of factors participate to modulate the viral lifecycle. Our lab is interested to understand the host-virus interaction and their precise role in modulation of pathogenesis. Recently, our lab has identified a non-canonical role of a host transcription factor STAT3 which has role contributing to viral replication. (Virus Res. 2021 Jul 15;300:198436). In another study, Our lab is elucidating the role of HMGB1 protein in dengue virus propagation. Thus the investigation in dengue host virus interaction with better understanding of transcription factors and cytokines, may provide a new dimension in developing effective control measures.
CHROMATIN REMODELLING
The packaging of DNA into nucleosomes and into chromatin fibers can take a range of functionally distinct forms. The regulation of chromatin environment is achieved by a complex web of factors by enzymes like chromatin remodellers which add and remove covalent modifications to histone proteins (resulting in various patterns of methylation, acetylation, phosphorylation, ubiquitination, etc.) and by ATP-dependent chromatin remodelers that assemble, move, and evict histones from DNA. By chemically modifying histone proteins and changing histone positioning on DNA, these factors create particular chromatin environments required for gene expression and silencing. Disruption of these factors cause severe imbalances in gene expression, and cancer. Our lab is trying to understand the role of chromodomain helicase DNA-binding chromatin remodelers CHD7, which has emerged as important regulators of cellular differentiation. CHD proteins are thought to function in the nucleus via binding to DNA and regulating gene transcription. CHD7, a member of the CHD family, encodes a protein mutated in human CHARGE syndrome, a multiple anomaly disorder. CHARGE syndrome is a multiple organ disorder that stands for Coloboma of eye, heart defects, atresia choanae, retarded growth, genital abnormality and ear abnormality. It occurs in approximately 1 in 8500 or 10,000 individuals. Mutations (frameshift and deletion) in CHD7 gene (located on chromosome 8), leads to the production of nonfunctional protein that interrupts chromatin remodelling of other genes involved in normal development and thus leads to the disorder. The identification of 7 heterozygous CHD7 stop-codon mutations and 2 single-copy 8q12 deletions of CHD7 gene designate that haploinsufficiency of this gene could account for most cases of CHARGE syndrome. CHARGE syndrome might also have a genetically heterogeneous etiology, as different genomic abnormalities have been identified in affected individuals.Our strategy is to obtain structural information of CHD7 using X-ray crystallography and cryoEM to understand the process of chromatin remodeling. Structural aspects of remodeler will be essential for defining precisely the molecular pathophysiology and scope of chromatin remodeling and epigenetics in human diseases. The structural understanding of chromatin remodelers may allow identifying targets, biomarkers and diagnostic tools relevant for biomedical application for novel therapeutics.
