Publications of NIPGR Scientists
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Item Epitope-directed anti-SARS-CoV-2 scFv engineered against the key spike protein region could block membrane fusion(John Wiley & Sons, 2023) Jaiswal, Deepika; Kumar, Ujjwal; Gaur, Vineet; Salunke, Dinakar M.The newly emerged SARS-CoV-2 causing coronavirus disease (COVID-19) resulted in >500 million infections. A great deal about the molecular processes of virus infection in the host is getting uncovered. Two sequential proteolytic cleavages of viral spike protein by host proteases are prerequisites for the entry of the virus into the host cell. The first cleavage occurs at S1/S2 site by the furin protease, and the second cleavage at a fusion activation site, the S2' site, by the TMPRSS2 protease. S2' cleavage site is present in the S2 domain of spike protein followed by a fusion peptide. Given the S2' site to be conserved among all the SARS-CoV-2 variants, we chose an S2' epitope encompassing the S2' cleavage site and generated single-chain antibodies (scFvs) through an exhaustive phage display library screening. Crystal structure of a scFv in complex with S2' epitope was determined. Incidentally, S2' epitope in the scFv bound structure adopts an alpha-helical conformation equivalent to the conformation of the epitope in the spike protein. Furthermore, these scFvs can bind to the spike protein expressed either in vitro or on the mammalian cell surface. We illustrate a molecular model based on structural and biochemical insights into the antibody-S2' epitope interaction emphasizing scFvs mediated blocking of virus entry into the host cell by restricting the access of TMPRSS2 protease and consequently inhibiting the S2' cleavage competitively.Item Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro(Royal Society of Chemistry, 2021) Panchariya, Love; Khan, Wajahat Ali; Kuila, Shobhan; Sonkar, Kirtishila; Sahoo, Sibasis; Ghoshal, Archita; Kumar, Ankit; Verma, Dileep Kumar; Hasan, Abdul; Khan, Mohd Azeem; Jain, Niyati; Mohapatra, Amit Kumar; Das, Shubhashis; Thakur, Jitendra K.; Maiti, Souvik; Nanda, Ranjan Kumar; Halder, Rajkumar; Sunil, Sujatha; Arockiasamy, ArulanduZinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with zinc demonstrate better clinical outcomes. The molecular targets and mechanistic details of the anti-coronaviral activity of zinc remain obscure. We show that zinc not only inhibits the SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of the Mpro–Zn2+ complex at 1.9 Å and provide the structural basis of viral replication inhibition. We show that Zn2+ coordinates with the catalytic dyad at the enzyme active site along with two previously unknown water molecules in a tetrahedral geometry to form a stable inhibited Mpro–Zn2+ complex. Further, the natural ionophore quercetin increases the anti-viral potency of Zn2+. As the catalytic dyad is highly conserved across SARS-CoV, MERS-CoV and all variants of SARS-CoV-2, Zn2+ mediated inhibition of Mpro may have wider implications.Item ROS/RNS Balancing, Aerobic Fermentation Regulation and Cell Cycle Control - a Complex Early Trait ('CoV-MAC-TED') for Combating SARS-CoV-2-Induced Cell Reprogramming(Frontiers Media S.A., 2021) Costa, José Hélio; Mohanapriya, Gunasekaran; Bharadwaj, Revuru; Noceda, Carlos; Thiers, Karine Leitão Lima; Aziz, Shahid; Srivastava, Shivani; Oliveira, Manuela; Gupta, Kapuganti Jagadis; Kumari, Aprajita; Sircar, Debabrata; Kumar, Sarma Rajeev; Achra, Arvind; Sathishkumar, Ramalingam; Adholeya, Alok; Arnholdt-Schmitt, BirgitIn a perspective entitled 'From plant survival under severe stress to anti-viral human defense' we raised and justified the hypothesis that transcript level profiles of justified target genes established from in vitro somatic embryogenesis (SE) induction in plants as a reference compared to virus-induced profiles can identify differential virus signatures that link to harmful reprogramming. A standard profile of selected genes named 'ReprogVirus' was proposed for in vitro-scanning of early virus-induced reprogramming in critical primary infected cells/tissues as target trait. For data collection, the 'ReprogVirus platform' was initiated. This initiative aims to identify in a common effort across scientific boundaries critical virus footprints from diverse virus origins and variants as a basis for anti-viral strategy design. This approach is open for validation and extension. In the present study, we initiated validation by experimental transcriptome data available in public domain combined with advancing plant wet lab research. We compared plant-adapted transcriptomes according to 'RegroVirus' complemented by alternative oxidase (AOX) genes during de novo programming under SE-inducing conditions with in vitro corona virus-induced transcriptome profiles. This approach enabled identifying a major complex trait for early de novo programming during SARS-CoV-2 infection, called 'CoV-MAC-TED'. It consists of unbalanced ROS/RNS levels, which are connected to increased aerobic fermentation that links to alpha-tubulin-based cell restructuration and progression of cell cycle. We conclude that anti-viral/anti-SARS-CoV-2 strategies need to rigorously target 'CoV-MAC-TED' in primary infected nose and mouth cells through prophylactic and very early therapeutic strategies. We also discuss potential strategies in the view of the beneficial role of AOX for resilient behavior in plants. Furthermore, following the general observation that ROS/RNS equilibration/redox homeostasis is of utmost importance at the very beginning of viral infection, we highlight that 'de-stressing' disease and social handling should be seen as essential part of anti-viral/anti-SARS-CoV-2 strategies.Item From plant survival under severe stress to anti-viral human defense - A perspective that calls for common efforts(Frontiers Media S.A., 2021) Arnholdt-Schmitt, Birgit; Mohanapriya, Gunasekaran; Bharadwaj, Revuru; Noceda, Carlos; Macedo, Elisete Santos; Sathishkumar, Ramalingam; Gupta, Kapuganti Jagadis; Sircar, Debabrata; Kumar, Sarma Rajeev; Srivastava, Shivani; Adholeya, Alok; Thiers, KarineLeitão Lima; Aziz, Shahid; Velada, Isabel; Oliveira, Manuela; Quaresma, Paulo; Achra, Arvind; Gupta, Nidhi; Kumar, Ashwani; Costa, Jose´ He´lioReprogramming of primary virus-infected cells is the critical step that turns viral attacks harmful to humans by initiating super-spreading at cell, organism and population levels. To develop early anti-viral therapies and proactive administration, it is important to understand the very first steps of this process. Plant somatic embryogenesis (SE) is the earliest and most studied model for de novo programming upon severe stress that, in contrast to virus attacks, promotes individual cell and organism survival. We argued that transcript level profiles of target genes established from in vitro SE induction as reference compared to virus-induced profiles can identify differential virus traits that link to harmful reprogramming. To validate this hypothesis, we selected a standard set of genes named 'ReprogVirus'. This approach was recently applied and published. It resulted in identifying 'CoV-MAC-TED', a complex trait that is promising to support combating SARS-CoV-2-induced cell reprogramming in primary infected nose and mouth cells. In this perspective, we aim to explain the rationale of our scientific approach. We are highlighting relevant background knowledge on SE, emphasize the role of alternative oxidase in plant reprogramming and resilience as a learning tool for designing human virus-defense strategies and, present the list of selected genes. As an outlook, we announce wider data collection in a 'ReprogVirus Platform' to support anti-viral strategy design through common efforts.Item Single virus targeting multiple organs: what we know and where we are heading?(Frontiers Media S.A., 2020) Prasad, Ashish; Prasad, ManojCOVID-19 caused by SARS-CoV-2 has already infected more than 6. 3 million people worldwide as of 1st June 2020 and caused a global medical emergency. Healthcare professionals have been struggling to devise appropriate therapeutic strategies against the virus mainly due to the diverse range of symptoms and multiple-organ failure in infected patients. Several broad-spectrum antiviral drugs are being used for treatment; however, there is yet no specific drug or vaccine against the virus. Multiple-organ failure due to hyperactivity of the immune system resulting in cytokine storms is a major reason for death among the 5% critically ill patients. In this article, we have discussed the damage caused by COVID-19 on different organs of the human body.Item Genomics approaches to synthesis plant-based biomolecules for therapeutic applications to combat SARS-CoV-2(Elsevier B.V., 2020) Sharma, Namisha; Muthamilarasan, Mehanathan; Prasad, Ashish; Prasad, ManojCOVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is devastative to the humankind for which neither vaccines nor precise therapeutic molecules for treatment are identified. The search for new drugs and repurposing of existing drugs are being performed; however, at the same time, research on plants to identify novel therapeutic compounds or testing the existing ones is progressing at a slower phase. In this context, genomics and biotechnology offer various tools and strategies to manipulate plants for producing those complex biopharmaceutical products. This review enumerates the scope for research on plant-based molecules for their potential application in treating SARS-CoV-2 infection. Strategies to edit gene and genome, overexpression and silencing approaches, and molecular breeding for producing target biomolecules in the plant system are discussed in detail. Altogether, the present review provides a roadmap for expediting research on using plants as a novel source of active biomolecules having therapeutic applications.Item Synergistic antiviral effects against SARS-CoV-2 by plant-based molecules(Springer Nature Publishing AG, 2020) Prasad, Ashish; Muthamilarasan, Mehanathan; Prasad, ManojThe exponential spread of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emphasizes the immediate need for efective antiviral drugs and vaccines that could control and prevent the spread of this pandemic. Several new and repurposed drugs are being tested for their efectiveness in the treatment regime, and the development of vaccines is underway. The availability of genome sequence information of the virus and the identifcation of potential targets to neutralize and eradicate the infection have enabled the search for novel as well as existing molecules to perform the desired function. However, the application of plants in the development of potential biomolecules, such as antibiotics and vaccines, is limited. Traditional medicines involving plant-based formulations have proven successful in boosting immunity and providing tolerance to virus infections. Still, in-depth studies are not available to explore the bioactive compounds of plant origin and their mechanism of action. Given this, the current opinion article conveys our thoughts and perspectives on the promising usage of plant-based biomolecules in circumventing SARS-CoV-2, and how these molecules can work synergistically with other potential drugs for treating SARS-CoV-2.Item SARS-CoV-2: the emergence of a viral pathogen causing havoc on human existence(Springer Nature Switzerland AG, 2020) Prasad, Ashish; Prasad, ManojCoronavirus disease 2019 was first reported from Wuhan district of China and has spread to 210 countries across the world claiming over 97,602 human lives as on 10 April 2020 by 21:06 pm. Currently, there is no specific treatment for this virus and the treatment is mainly relied on controlling symptoms. Here we discuss our current understanding of SARS-CoV-2 with respect to its receptor recognition and how this knowledge could be useful in treatement using clinically known inhibitory drugs. We have also discussed the diagnosis, treatment and preventive measures that are currently being employed for controlling further spread of the virus.