Publications by authors named "Manju Narwal"

The processing of the Coronavirus polyproteins pp1a and pp1ab by the main protease M to produce mature proteins is a crucial event in virus replication and a promising target for antiviral drug development. M cleaves polyproteins in a defined order, but how M and/or the polyproteins determine the order of cleavage remains enigmatic due to a lack of structural information about polyprotein-bound M. Here, we present the cryo-EM structures of SARS-CoV-2 M in an apo form and in complex with the nsp7-10 region of the pp1a polyprotein.

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SARS-CoV-2 proteases Mpro and PLpro are promising targets for antiviral drug development. In this study, we present an antiviral screening strategy involving a novel in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations for rapid identification of protease inhibitors with low cytotoxicity. We identified eight compounds with anti-SARS-CoV-2 activity from a library of 64 repurposed drugs and modeled at protease active sites by in silico docking.

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Chikungunya virus has emerged as one of the most important global arboviral threats over the last decade. Inspite of large scale morbidity, with long lasting polyarthralgia, so far no licensed vaccine or antiviral is available. CHIKV nsP2 protease is crucial for processing of viral nonstructural polypeptide precursor to release enzymes required for viral replication, thus making it a promising drug target.

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Alphavirus non-structural protein, nsP1 has a distinct molecular mechanism of capping the viral RNAs than the conventional capping mechanism of host. Thus, alphavirus capping enzyme nsP1 is a potential drug target. nsP1 catalyzes the methylation of guanosine triphosphate (GTP) by transferring the methyl group from S-adenosylmethionine (SAM) to a GTP molecule at its N7 position with the help of nsP1 methyltransferase (MTase) followed by guanylylation (GT) reaction which involves the formation of mGMP-nsP1 covalent complex by nsP1 guanylyltransferase (GTase).

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Article Synopsis
  • Chikungunya virus (CHIKV) poses a significant public health threat, and currently, there are no approved vaccines or antiviral treatments available.
  • The study focuses on nsP2pro, a viral protease crucial for the replication of CHIKV, revealing its crystal structure and highlighting its two main subdomains: a protease subdomain and a methyltransferase subdomain.
  • Key findings include that a flexible loop in the protein blocks access to its active site, and a specific mutation in one of the binding residues significantly impacts substrate recognition, providing insights for potential drug development targeting this protease.
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Chikungunya virus (CHIKV), a mosquito-borne pathogenic virus that reemerged and caused epidemic in the Indian Ocean island of La Réunion, is a potential public health threat. Currently there is no antiviral drug or vaccine commercially available for the treatment of chikungunya fever, which necessitates the urge for an effective antiviral therapy for chikungunya treatment. In the present study, a FRET based protease assay was used to analyze the proteolytic activity of chikungunya nsP2 protease (CHIKV nsP2pro) - an essential viral enzyme, with fluorogenic substrate peptide.

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Article Synopsis
  • DAHPS is the first enzyme in the shikimate pathway, crucial for synthesizing aromatic amino acids in microorganisms, making it a potential target for antimicrobial drug development.
  • The first structure of the AroQ class chorismate mutase (BsCM_2) from Bacillus subtilis was determined in complex with citrate and chlorogenic acid, revealing important details about ligand binding and active site flexibility.
  • Molecular dynamics show that certain conformational changes in the enzyme's structure may influence DAHPS regulation, highlighting chlorogenic acid's higher binding affinity compared to chorismate, which could aid in creating new antimicrobial therapies.
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Lipopolysaccharide (LPS) is an important surface component and a potential virulence factor in the pathogenesis of Gram-negative bacteria. UDP-N-acetylglucosamine acyltransferase (LpxA) enzyme catalyzes the first reaction of LPS biosynthesis, reversible transfer of R-3-hydroxy-acyl moiety from donor R-3-hydroxy-acyl-acyl carrier protein to the 3' hydroxyl position of UDP-N-acetyl-glucosamine. LpxA enzyme's essentiality in bacterial survival and absence of any homologous protein in humans makes it a promising target for anti-bacterial drug development.

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The rise of multiple-drug resistance in bacterial pathogens imposes a serious public health concern and has led to increased interest in studying various pathways as well as enzymes. Different DNA glycosylases collaborate during bacterial infection and disease by overcoming the effects of ROS- and RNS-mediated host innate immunity response. 3-Methyladenine DNA glycosylase I, an essential DNA repair enzyme, was chosen for the present study from the MDR species of A.

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Alphavirus nonstructural protein nsP1 possesses distinct methyltransferase (MTase) and guanylyltransferase (GTase) activities involved in the capping of viral RNAs. In alphaviruses, the methylation of GTP occurs before RNA transguanylation and nsP1 forms a covalent complex with m(7)GMP unlike the host mRNA guanylyltransferase which forms GMP-enzyme complex. In this study, full length SINV nsP1 was expressed in a soluble form with an N-terminal histidine tag in Escherichia coli and purified to homogeneity.

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