The lab is working on:
The COVID-19 pandemic caused by SARS-CoV-2 has emerged as a global catastrophe. The virus requires main protease for processing the viral polyproteins PP1A and PP1AB translated from the viral RNA. In search of a quick, safe and successful therapeutic agent; we screened various clinically approved drugs for the in-vitro inhibitory effect on 3CLPro which may be able to halt virus replication. In our lab, we have used methods protease activity assay, fluorescence quenching, surface plasmon resonance (SPR), Thermofluor® Assay, Size exclusion chromatography and in-silico docking studies for screening and evaluating molecules against main protease of SARS-CoV-2. We found that Teicoplanin as most effective drug with relatively high affinity between Teicoplanin and 3CLPro protease. We studied protein-drug interactions in order to decipher the working of the drug and mechanism of inhibition at the molecular level. Our results provide critical insights into the mechanism of action of Teicoplanin as a potential therapeutic against COVID-19. We found that Teicoplanin is about 10–20 fold more potent in inhibiting protease activity than other drugs in use. Therefore, Teicoplanin emerged as the best inhibitor among all drug molecules we screened against 3CLPro of SARS-CoV-2. The approved drug Teicoplanin has already been tested for toxicity in human beings over a period of time. We propose Teicoplanin as an effective drug against SARS CoV-2. The study paves the path for expedited research to an effective treatment of COVID-19. We also propose immediate attention for the animal experiments and randomized clinical trials for this drug to reduce infections and to help the society, as it has a proven mechanism of action and efficacy as compared to other recommended drugs for COVID-19.
lab is involved in Screening and evaluation of approved molecules and medicinal herbs for antiviral activity against chikungunya targeting its non-structural protein-2.
Dengue virus (DENV) is most prevalent arthropod-borne human pathogen belongs to Flaviviridae family causes thousands of deaths annually. HMGB1 is highly conserved, ubiquitously expressed, non-histone nuclear protein which plays important role in diseases like metabolic disorders, cancer, and viral infections. However, the importance of HMGB1 in DENV infection is understudied. Our lab has observed that DENV-2 induces cytoplasmic translocation and secretion of HMGB1. Our finding suggests that DENV-2 modulates HMGB1 translocation and HMGB1-DENV-2 UTRs RNA interaction further induces proinflammatory cytokines production in A549 cells. This study discloses HMGB1 as an important host factor contributing to disease pathogenesis and hence can be targeted as an alternative approach for antiviral development against DENV virus infection. Dengue virus (DENV) exploits various cellular pathways including autophagy to assure enhanced virus propagation. The mechanisms of DENV mediated control of autophagy pathway are largely unknown. Our investigations have revealed a novel role for high-mobility group box1 protein (HMGB1) in regulation of cellular autophagy process in DENV-2 infected A549 cell line. Our study shows that the modulation of autophagy by DENV-2 is HMGB1/BECN1 dependent. Altogether, our data suggests that HMGB1 induces BECN1 dependent autophagy to promote DENV-2 replication.
Further lab is interested to know how DENV has evolved to evade elimination by the host antiviral immune system. DENV is reported to modulate host interferon response either by attenuating the factors that mediate interferon response like STAT1 and STAT2 or inhibiting the activation of STAT1 or by STAT2 degradation. Our study aimed to understand how DENV modulates STAT3 mediated interferon response to its own advantage. We employed various techniques like Western blot, Confocal microscopy, RT-PCR to show that STAT3 acts as a pro-viral factor for DV-2 propagation. As per result of the present study STAT3 is upregulated as well as activated by phosphorylation in DV-2 infected A549 cells. Additionally, STAT3 knockdown led to a significant decrease in expression of viral proteins as well as viral replication. We show that DV-2 strategically tweaks STAT3 which is a negative regulator of Type I IFN signaling, in order to evade host Type I and Type III interferon response by upregulating its expression and activation. Our results demonstrate the proviral role of STAT3 for DV-2 propagation which is correlated to activation by tyrosine phosphorylation. Furthermore, since STAT3 is critical factor for DV-2 propagation, its modulation can facilitate targeted development of antivirals against Dengue.
Our lab is interested in understanding how activation of innate receptors in megakaryocytes (MKs) may affect the ability to produce functional platelets. Low platelet count is one of the clinical manifestations of dengue virus (DENV) infection. In MKs, the effect of innate receptors during DENV-infection is not well studied. Our lab used MEG-01 cells to investigate DENV serotype 2 induced innate receptors in these cells. DENV infection led to increased expression of RIG-I and MDA-5. However, no change in the expression of TLR3 at protein level was observed. Activation of MDA-5 resulted in increased expression of IFN-β and ISG-15 in DENV infected MEG-01 cells, which was further confirmed by MDA-5 siRNA treatment. Apart from inducing innate receptors, DENV significantly decreases the expression of CD61, an activation marker of megakaryocytes on MEG-01 cells as observed by flow cytometry analysis. Results from our study confirm that DENV infection activates the type-I interferon in megakaryocytes and may play a significant role in maturation and development.