Biology subjects

Kumar, S.

Publications and source records attributed to Kumar, S..

At least 595 records · Page 33Linked to original sources

bioRxiv2020

Sphingolipid Biosynthesis Inhibition As A Host Strategy Against Diverse Pathogens

Chloroquine is an anti-malarial and immunosuppressant drug that has cationic amphipathic chemical properties. We performed genome-wide screens in human cells with chloroquine and several other widely used cationic amphipathic drugs (CADs) including the anti-depressants, sertraline (Zoloft) and fluoxetine (Prozac), the analgesic nortriptyline (Pamelor), the anti-arrhythmic amiodarone (Cordarone), and the anti-hypertensive verapamil (Calan) to characterize their molecular similarities and differences. Despite CADs having different disease indications but consistent with them sharing key chemical properties, we found CADs to have remarkably similar phenotypic profiles compared with non-CADs we and others have previously screened (1-5). The most significant genetic interaction for all CADs was the initiating step in sphingolipid biosynthesis catalyzed by serine palmitoyltransferase (SPT). A comparison of genome-wide screens performed with diverse pathogens from viruses, bacteria, plants, and parasites including Ebola (6), adeno-associated virus AAV2 (7), HIV (8), Rotavirus (9), Influenza A (10), Zika virus (11), Picornavirus (12), Exotoxin A (13), Cholera toxin (14), Type III secretion system and Shiga toxin (15, 16), Ricin toxin (17), and Toxoplasma gondii (18) showed SPT as a top common host factor and 80% overlap overall in top hits specifically with CADs. Potential sphingolipid-mediated mechanisms for the host response- and virulence-modulating effects of CADs involve autophagy and SERPINE1/PAI-1 (plasminogen activator inhibitor-1). Chloroquine has recently shown potential as an anti-viral agent for the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease (19, 20). Our study demonstrates that numerous readily available drugs molecularly function highly similar to chloroquine, which suggests they might be considered for further pre-clinical investigation in the context of SARS-CoV-2. More generally, our work suggests the diverse pathogen mitigating potential of drugs that inhibit host sphingolipid biosynthesis such as CADs. Brief SummaryOur study demonstrates that numerous readily available drugs molecularly function highly similar to chloroquine, which suggests they might be considered for further pre-clinical investigation in the context of SARS-CoV-2.

genomics↗

bioRxiv2020

HSPs, Ubiquitins and Antioxidants aid in Heat Tolerance in Tharparkar Indicine cattle

Transcriptome profiling of Vrindavani and Tharparkar cattle revealed that more numbers of genes dysregulated in Vrindavani than in Tharparkar. A contrast in gene expression was observed with 18.5 % of upregulated genes in Vrindavani were downregulated in Tharparkar and 17.5% upregulated genes in Tharparkar were downregulated in Vrindavani. Functional annotation of genes differentially expressed in Tharparkar and Vrindavani revealed that the systems biology in Tharparkar is moving towards counteracting the effects due to heat stress. Unlike Vrindavani, Tharparkar is not only endowed with higher expression of the scavengers (UBE2G1, UBE2S, and UBE2H) of misfolded proteins but also with protectors (VCP, Serp1, and CALR) of naive unfolded proteins. Further, higher expression of the antioxidants in Tharparkar enables it to cope up with higher levels of free radicals generated as a result of heat stress. In this study we found relevant genes dysregulated in Tharparkar in the direction that can counter heat stress.

physiology↗

bioRxiv2020

Understanding the B and T cells epitopes of spike protein of severe respiratory syndrome coronavirus-2: A computational way to predict the immunogens

The 2019 novel severe respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak has caused a large number of deaths with thousands of confirmed cases worldwide. The present study followed computational approaches to identify B- and T-cell epitopes for spike glycoprotein of SARS-CoV-2 by its interactions with the human leukocyte antigen alleles. We identified twenty-four peptide stretches on the SARS-CoV-2 spike protein that are well conserved among the reported strains. The S protein structure further validated the presence of predicted peptides on the surface. Out of which twenty are surface exposed and predicted to have reasonable epitope binding efficiency. The work could be useful for understanding the immunodominant regions in the surface protein of SARS-CoV-2 and could potentially help in designing some peptide-based diagnostics.

microbiology↗

bioRxiv2020

Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. We previously demonstrated that four nucleotide analogues (specifically, the active triphosphate forms of Sofosbuvir, Alovudine, AZT and Tenofovir alafenamide) inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Tenofovir and emtricitabine are the two components in DESCOVY and TRUVADA, the two FDA-approved medications for use as pre-exposure prophylaxis (PrEP) to prevent HIV infection. This is a preventative method in which individuals who are HIV negative (but at high-risk of contracting the virus) take the combination drug daily to reduce the chance of becoming infected with HIV. PrEP can stop HIV from replicating and spreading throughout the body. We report here that the triphosphates of tenofovir and emtricitabine, the two components in DESCOVY and TRUVADA, act as terminators for the SARS-CoV-2 RdRp catalyzed reaction. These results provide a molecular basis to evaluate the potential of DESCOVY and TRUVADA as PrEP for COVID-19.

pharmacology and toxicology↗

bioRxiv2020

Hyperactive end joining repair mediates resistance to DNA damaging therapy in p53-deficient cells

TP53 mutations in cancer are associated with poor patient outcomes and resistance to DNA damaging therapies1-3. However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Here, we show that p53-deficient cells exhibit hyperactive repair of therapy-induced DNA double strand breaks (DSBs), which is suppressed by inhibition of DNA-dependent protein kinase (DNA-PK). Single-cell analyses of DSB repair kinetics and cell cycle state transitions reveal an essential role for DNA-PK in suppressing S phase DNA damage and mitotic catastrophe in p53-deficient cells. Yet, a subset of p53-deficient cells exhibit intrinsic resistance to therapeutic DSBs due to a repair pathway that is not sensitive to DNA-PK inhibition. We show that p53 deficiency induces overexpression of DNA Polymerase Theta (Pol {theta}), which mediates an alternative end-joining repair pathway that becomes hyperactivated by DNA-PK inhibition4. Combined inhibition of DNA-PK and Pol {theta} restores therapeutic DNA damage sensitivity in p53-deficient cells. Thus, our study identifies two targetable DSB end joining pathways that can be suppressed as a strategy to overcome resistance to DNA-damaging therapies in p53-deficient cancers.

cell biology↗

bioRxiv2020

Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C drug EPCLUSA), is incorporated by SARS-CoV-2 RdRp, and blocks further incorporation. Using the same molecular insight, we selected the active triphosphate forms of three other anti-viral agents, Alovudine, AZT (an FDA approved HIV/AIDS drug) and Tenofovir alafenamide (TAF, an FDA approved drug for HIV and hepatitis B) for evaluation as inhibitors of SARS-CoV-2 RdRp. We demonstrated the ability of these three viral polymerase inhibitors, 3-fluoro-3-deoxythymidine triphosphate, 3-azido-3-deoxythymidine triphosphate and Tenofovir diphosphate (the active triphosphate forms of Alovudine, AZT and TAF, respectively) to be incorporated by SARS-CoV-2 RdRp, where they also terminate further polymerase extension. These results offer a strong molecular basis for these nucleotide analogues to be evaluated as potential therapeutics for COVID-19.

pharmacology and toxicology↗

bioRxiv2020

RRBP1 rewires cisplatin resistance in Oral Squamous Cell Carcinoma by regulating YAP-1

Cisplatin-based chemotherapy still remains as one of the primary treatment modalities for OSCC. Several OSCC patients experience relapse owing to development of chemoresistance. To identify key resistance triggering molecules, we performed global proteomic profiling of human OSCC lines presenting with sensitive, early and late cisplatin resistance patterns. From the proteomic profiling study, human RRBP1 was identified to be upregulated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient sample indicates that RRBP1 expression is elevated in chemotherapy-non-responder tumors as compared to chemotherapy-naive tumors. Knocking out RRBP1 resulted in restoring cisplatin mediated cell death in chemoresistant lines and patient derived cells (PDC). Mechanistically, RRBP1 regulates YAP-1 to induce chemoresistance in OSCC. The chemoresistant PDC xenograft data suggests that knock out of RRBP1 induces cisplatin mediated cell death and facilitates a significant reduction of tumor burden. We also found Radezolid, a novel oxazolidinone antibiotic represses the expression of RRBP1 and restores cisplatin-induced cell death in chemoresistant OSCC. This unique combinatorial approach needs further clinical investigation to target advanced OSCC. Here with for the first time, we uncover the novel role of RRBP1 as potential modulator of cisplatin resistance in advanced OSCC.

cancer biology↗

bioRxiv2020

Nucleotide Analogues as Inhibitors of SARS-CoV Polymerase

SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency.1 Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved heptatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2.2 Here, using model polymerase extension experiments, we demonstrate that the activated triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the activated triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected two other anti-viral agents, Alovudine and AZT (an FDA approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two HIV reverse transcriptase inhibitors, 3-fluoro-3-deoxythymidine triphosphate and 3-azido-3-deoxythymidine triphosphate (the active triphosphate forms of Alovudine and AZT), to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.

pharmacology and toxicology↗

bioRxiv2020

Phosphorylation by Aurora B kinase regulates caspase-2 activity and function

Mitotic catastrophe (MC) is an important oncosuppressive mechanism that serves to eliminate cells that become polyploid or aneuploidy due to aberrant mitosis. Previous studies have demonstrated that the activation and catalytic function of caspase-2 are key steps in MC to trigger apoptosis and/or cell cycle arrest of mitotically defective cells. However, the molecular mechanisms that regulate caspase-2 activation and its function are unclear. Here we identify six new phosphorylation sites in caspase-2 and show that a key mitotic kinase, Aurora B kinase (AURKB), phosphorylates caspase-2 at the highly conserved residue S384. We demonstrate that phosphorylation at S384 blocks caspase-2 catalytic activity and apoptosis function in response to mitotic insults, without affecting caspase-2 dimerisation. Moreover, molecular modelling suggests that phosphorylation at S384 may affect substrate binding by caspase-2. We propose that caspase-2 S384 phosphorylation by AURKB is a key mechanism that controls caspase-2 activation during mitosis.

cell biology↗

bioRxiv2020

The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of the glucagon-like peptide-1 receptor (GLP-1R) in type 2 diabetes and obesity. In the present study, we have evaluated a peptide series with varying sequence homology between native GLP-1 and exendin-4, the archetypal ligands on which approved GLP-1R agonists are based. We find notable differences in agonist-mediated signalling, endocytosis and recycling, dependent both on the introduction of a His [->] Phe switch at position 1 and the specific mid-peptide helical regions and C-termini of the two agonists. These observations were linked to insulin secretion in a beta cell model and provide insights into how ligand factors influence GLP-1R function at the cellular level. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/961524v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@cb425borg.highwire.dtl.DTLVardef@719e37org.highwire.dtl.DTLVardef@14a45b9org.highwire.dtl.DTLVardef@127afd1_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2020

The transcriptional landscape of Venezuelan equine encephalitis virus infection

Venezuelan Equine Encephalitis Virus (VEEV) is a major biothreat agent that naturally causes outbreaks in humans and horses particularly in tropical areas of the western hemisphere, for which no antiviral therapy is currently available. The host response to VEEV and the cellular factors this alphavirus hijacks to support its effective replication or evade cellular immune responses are largely uncharacterized. We have previously demonstrated tremendous cell-to-cell heterogeneity in viral RNA (vRNA) and cellular transcript levels during flaviviral infection using a novel virus-inclusive single-cell RNA-Seq approach. Here, we used this unbiased, genome-wide approach to simultaneously profile the host transcriptome and vRNA in thousands of single cells during infection of human astrocytes with the live-attenuated vaccine strain of VEEV (TC-83). Host transcription was profoundly suppressed, yet "superproducer cells" with extremely high vRNA abundance emerged during the first viral life cycle and demonstrated an altered transcriptome relative to both uninfected cells and cells with high vRNA abundance harvested at later time points. Additionally, cells with increased structural-to-nonstructural transcript ratio exhibited upregulation of intracellular membrane trafficking genes at later time points. Loss- and gain-of-function experiments confirmed pro- and antiviral activities in both vaccine and virulent VEEV infections among the products of transcripts that positively or negatively correlated with vRNA abundance, respectively. Lastly, comparison with single cell transcriptomic data from other viruses highlighted common and unique pathways perturbed by infection across evolutionary scales. This study provides a high-resolution characterization of the VEEV (TC-83)-host interplay, identifies candidate targets for antivirals, and establishes a comparative single-cell approach to study the evolution of virus-host interactions. Author SummaryLittle is known about the host response to Venezuelan Equine Encephalitis Virus (VEEV) and the cellular factors this alphavirus hijacks to support effective replication or evade cellular immune responses. Monitoring dynamics of host and viral RNA (vRNA) during viral infection at a single-cell level can provide insight into the virus-host interplay at a high resolution. Here, a single-cell RNA sequencing technology that detects host and viral RNA was used to investigate the interactions between TC-83, the vaccine strain of VEEV, with the human host during the course of infection of U-87 MG cells (human astrocytoma). Virus abundance and host transcriptome were heterogeneous across cells from the same culture. Subsets of differentially expressed genes, positively or negatively correlating with vRNA abundance, were identified and subsequently in vitro validated as candidate proviral and antiviral factors, respectively, in TC-83 and/or virulent VEEV infections. In the first replication cycle, "superproducer" cells exhibited rapid increase in vRNA abundance and unique gene expression patterns. At later time points, cells with increased structural-to-nonstructural transcript ratio demonstrated upregulation of intracellular membrane trafficking genes. Lastly, comparing the VEEV dataset with published datasets on other RNA viruses revealed unique and overlapping responses across viral clades. Overall, this study improves the understanding of VEEV-host interactions, reveals candidate targets for antiviral approaches, and establishes a comparative single-cell approach to study the evolution of virus-host interactions.

microbiology↗

bioRxiv2020

Identification of potential candidates for drug designing against Klebsiella Pneumoniae among hypothetical proteins of DNA Adenine Methyltransferase through subtractive genomics approach

Klebsiella Pneumoniae is a gram-negative bacterium that is known for causing infection in nosocomial settings. As reported by WHO, this bacterial pathogen is classified as an urgent threat our most concern is that these bacterial pathogens acquired genetic traits that make them resistant towards antibiotics. The last class of antibiotics; carbapenems are not able to combat these bacterial pathogens allowing them to clonally expand their antibiotic-resistant strain. Most antibiotics target the essential pathways of the bacteria cell however these targets are no longer susceptible to the antibiotic. Hence in our study, we focus on Klebsiella Pneumoniae bacterial strains that contain DNA Adenine Methyltransferase domain which suggests a new potential site for a drug target. DNA methylation is seen to regulate the attenuation of bacterial virulence. In this study, all hypothetical proteins of Klebsiella Pneumoniae containing N6 DNA Adenine Methyltransferase domain were analysed for a potential drug target. About 32 hypothetical proteins were retrieved from Uniprot. 19 proteins were selected through a step-wise subtractive genomics approach like a selection of non-homologus proteins against the human host, selection of bacterial proteins contains an essential gene, broad-spectrum analysis, druggability analysis, Non-homology analysis against gut microbiota. Through drug target prioritization like sub-cellular analysis, drug property analysis, anti-target non-homology analysis, virulence factor analysis and protein-protein interaction analysis one drug target protein (Uniprot ID: A0A2U0NNR3) was prioritized. Identified drug target docked with potential inhibitors like are mahanine (PubChem ID: 375151), curcumin (PubChem ID: 969516), EGCG (PubChem ID: 65064), nanaomycin A (PubChem ID: 40586), parthenolide (PubChem ID: 7251185), quercetin (PubChem ID: 5280343) and trimethylaurintricarboxylic acid. Based on the moelcular docking analysis, mahanine has the highest binding affinity. In order to identify novel natural inhibitor based on mahanine fingerprint search is performed against NPASS (Natural Product Activity and Species Source databases) and Koenimbine was identified as a novel natural inhibitor based on virtual screening.

bioinformatics↗

bioRxiv2020

Relative efficiencies of simple and complex substitution models in estimating divergence times in phylogenomics

The conventional wisdom in molecular evolution is to apply parameter-rich models of nucleotide and amino acid substitutions for estimating divergence times. However, the actual extent of the difference between time estimates produced by highly complex models compared to those from simple models is yet to be quantified for contemporary datasets that frequently contain sequences from many species and genes. In a reanalysis of many large multispecies alignments from diverse groups of taxa using the same tree topologies and calibrations, we found that the use of the simplest models can produce divergence time estimates and credibility intervals similar to those obtained from the complex models applied in the original studies. This result is surprising because the use of simple models underestimates sequence divergence for all the datasets analyzed. We find three fundamental reasons for the observed robustness of time estimates to model complexity in many practical datasets. First, the estimates of branch lengths and node-to-tip distances under the simplest model show an approximately linear relationship with those produced by using the most complex models applied, especially for datasets with many sequences. Second, relaxed clock methods automatically adjust rates on branches that experience considerable underestimation of sequence divergences, resulting in time estimates that are similar to those from complex models. And, third, the inclusion of even a few good calibrations in an analysis can reduce the difference in time estimates from simple and complex models. The robustness of time estimates to models complexity in these empirical data analyses is encouraging, because all phylogenomics studies use statistical models that are oversimplified descriptions of actual evolutionary substitution processes.

evolutionary biology↗

bioRxiv2020

Molecular control of interfacial protein structure on graphene-based substrates steers cell fate

The use of graphene-based materials (GBMs) for tissue-engineering applications is growing exponentially due to the seemingly endless multi-functional and tunable physicochemical properties of graphene, which can be exploited to influence cellular behaviours. Despite many demonstrations wherein cell physiology can be modulated on GBMs, a clear mechanism connecting the different physicochemical properties of different GBMs to cell fate has remained elusive. In this work, we demonstrate how different GBMs can be used to cell fate in a multi-scale study - starting from serum protein (Fibronectin) adsorption to molecular scale morphology, structure and bioactivity, and finally ending with stem cell response. By changing the surface chemistry of graphene substrates with only heating, we show that molecular conformation and morphology of surface adsorbed fibronectin controls epitope presentation, integrin binding, and stem cell attachment. Moreover, this subtle change in protein structure is found to drive increased bone differentiation of cells, suggesting that physicochemical properties of graphene substrates exert cell control by influencing adsorbed protein structure.

bioengineering↗

bioRxiv2020

Supervised and Unsupervised Classification of Cocoa Bean Origin and Processing using Liquid Chromatography-Mass Spectrometry

Liquid Chromatography-Mass Spectrometry (LC-MS) provides an unprecedented wealth of metabolomics information for food products, including insights into compositional changes during food processing. Here, we employed the largest available LC-MS dataset of around 300 cocoa bean samples to assess the capability of two popular multivariate classification methods, principal component analysis (PCA) and linear decomposition analysis (LDA), for studying bean geographic origin and responsible characteristic compounds. The unsupervised method, PCA, only provides a limited separation in bean origin. Expectedly, the supervised method, LDA, provides a better origin clustering. However, it suffers from a strong, nonlinear dependence on the set of compounds used in the analysis. We show that for LDA a compound filtering criterion based on Gaussian intensity distributions dramatically enhances origin clustering of samples, thus increasing its predictive efficiency. In this form, the supervised method of LDA holds the possibility to identify potential markers of a specific origin.

bioinformatics↗

bioRxiv2020

Correlation network analysis based on untargeted LC-MS profiles of cocoa reveals processing stage and origin country

In order to implement quality control measures and create fine flavor products, an important objective in cocoa processing industry is to realize standards for characterization of cocoa raw materials, intermediate and finished products with respect to their processing stages and countries of origin. Towards this end, various works have studied separability or distinguishability of cocoa samples belonging to various processing stages in a typical cocoa processing pipeline or to different origins. Limited amount of success has been possible in this direction in that unfermented and fermented cocoa samples have been shown to group into separate clusters in PCA. However, a clear clustering with respect to the country of origin has remained elusive. In this work we suggest an alternative approach to this problem through the framework of correlation networks. For 140 cocoa samples belonging to eight countries and three progressive stages in a typical cocoa processing pipeline we compute pairwise Spearman and Pearson correlation coefficients based on the LC-MS profiles and derive correlation networks by retaining only correlations higher than a threshold. Progressively increasing this threshold reveals, first, processing stage (or sample type) modules (or network clusters) at low and intermediate values of correlation threshold and then country specific modules at high correlation thresholds. We present both qualitative and quantitative evidence through network visualization and node connectivity statistics. Besides demonstrating separability of the two data properties via this network-based method, our work suggests a new approach for studying classification of cocoa samples with nested attributes of processing stage sample types and country of origin along with possibility of including additional factors, e.g., hybrid variety, etc. in the analysis.

systems biology↗

bioRxiv2020

Deep phylo-taxono-genomics (DEEPT genomics) reveals misclassification of Xanthomonas species complexes into Xylella, Stenotrophomonas and Pseudoxanthomonas

Genus Xanthomonas encompasses specialized group of phytopathogenic bacteria with genera Xylella, Stenotrophomonas and Pseudoxanthomonas being its closest relatives. While species of genera Xanthomonas and Xylella are known as serious phytopathogens, members of other two genera are found in diverse habitats with metabolic versatility of biotechnological importance. Few species of Stenotrophomonas are multidrug resistant opportunistic nosocomial pathogens. In the present study, we report genomic resource of genus Pseudoxanthomonas and further in-depth comparative studies with publically available genome resources of other three genera. Surprisingly, based on deep phylo-taxono-genomic or DEEPT criteria, all the four genera were found to be one genus and hence synonyms of Xanthomonas. The members of Pseudoxanthomonas are more diverse and ancestral and rest forming two mega species groups (MSGs) i.e. Xanthomonas Xylella (XX-MSG) and Stenotrophomonas (S-MSG). Within XX-MSG, there are 3 species complexes i.e., X. citri complex (Xcc) member species are primarily pathogenic to dicots, X. hyacinthi complex (Xhc) member species are primarily pathogenic to monocots and Xanthomonas (Xylella) fastidosa complex (Xfc) with diverse phytopathogenic potential. Interestingly, Xylella seems to be a variant Xanthomonas lineage or species complex that is sandwiched between Xcc and Xhc. Like Xylella, within S-MSG, we find a species complex of clinical origin Xanthomonas (Stenotrophomonas) maltophilia complex (Xmc). Comparative studies revealed selection and role of xanthomonadin pigment and xanthan gum in emergence of plant pathogenic XX-MSG. Pan genome analysis also revealed large set of unique genes with particular functions suited for plant/animal lifestyle responsible for emergence of variant Xfc and Xmc species complexes. Overall, our systematic and large scale genera based study has allowed us to understand the origin and to clarify the taxonomic breadth of genus of high importance in agriculture, medicine and industry. Such DEEPT genomics studies are also way forward to identify right markers or functions for diagnosis and drug development of any pathogenic bacteria. RepositoriesGenome Submission Accession Number: MWIP00000000, PDWO00000000, PDWN00000000, PDWT00000000, PDWS00000000, PDWW00000000, PDWU00000000, PDWR00000000, PDWL00000000, PDWQ00000000, PDWM00000000, PDWP00000000, PDWV00000000, PDWK00000000 and QOVG00000000

genomics↗

bioRxiv2020

Nucleotide Analogues as Inhibitors of Viral Polymerases

Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies. Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents, we further describe a novel strategy to design and synthesize viral polymerase inhibitors, by combining the ProTide Prodrug approach used in the development of Sofosbuvir with the use of 3-blocking groups that we have previously built into nucleotide analogues that function as polymerase terminators.

pharmacology and toxicology↗