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    Mutation Landscape of SARS COV2 in Africa

    Authors: Angus A Nassir; Clarisse Musanabaganwa; Ivan Mwikarago; Vanessa Blanc; Joan Gispert; Bonventura Clotet; Nuria Izquierdo-Useros; Darryl Hill; Paolo Madeddu; Shawn A Abbasi; Whitney Pickens; Katia George; Daniel R Boutz; Dalton M Towers; Jonathan R McDaniel; Daniel Billick; Jule Goike; Lori Rowe; Dhwani Batra; Jan Pohl; Justin Lee; Shivaprakash Gangappa; Suryaprakash Sambhara; Michelle Gadush; Nianshuang Wang; Maria D Person; Brent L Iverson; Jimmy D Gollihar; John Dye; Andrew Herbert; Ralph S Baric; Jason S McLellan; George Georgiou; Jason J Lavinder; Gregory C Ippolito; Fergus Gleeson; Yper Hall; Simon G. P. Funnell; Sally Sharpe; Francisco Javier Salguero; Andrew R Gorringe; Miles Carroll

    doi:10.1101/2020.12.20.423630 Date: 2020-12-21 Source: bioRxiv

    COVID-19 MESHD disease has had a relatively less severe impact in Africa. To understand the role of SARS CoV2 mutations on COVID-19 MESHD disease in Africa, we analysed 282 complete nucleotide sequences from African isolates deposited in the NCBI Virus Database. Sequences were aligned against the prototype Wuhan sequence (GenBank accession: NC_045512.2) in BWA v. 0.7.17. SAM and BAM files were created, sorted and indexed in SAMtools v. 1.10 and marked for duplicates using Picard v. 2.23.4. Variants were called with mpileup in BCFtools v. 1.11. Phylograms were created using Mr. Bayes v 3.2.6. A total of 2,349 single nucleotide polymorphism (SNP) profiles across 294 sites were identified. Clades associated with severe disease in the United States, France, Italy, and Brazil had low frequencies in Africa (L84S=2.5%, L3606F=1.4%, L3606F/V378I/=0.35, G251V=2%). Sub Saharan Africa (SSA) accounted for only 3% of P323L and 4% of Q57H mutations in Africa. Comparatively low infections MESHD in SSA were attributed to the low frequency of the D614G clade in earlier samples (25% vs 67% global). Higher disease burden occurred in countries with higher D614G frequencies (Egypt=98%, Morocco=90%, Tunisia=52%, South Africa) with D614G as the first confirmed case. V367F, D364Y, V483A and G476S mutations associated with efficient ACE2 HGNC receptor binding and severe disease were not observed in Africa. 95% of all RdRp PROTEIN mutations were deaminations leading to CpG depletion and possible attenuation of virulence. More genomic and experimental studies are needed to increase our understanding of the temporal evolution of the virus in Africa, clarify our findings, and reveal hot spots that may undermine successful therapeutic and vaccine interventions.

    Genetic Conservation of SARS-CoV-2 RNA Replication Complex in Globally Circulating Isolates from Humans and Minks Predicts Minimal Pre-Existing Resistance to Remdesivir

    Authors: Ross Martin; Jason Perry; Tomas Cihlar; Hongmei Mo; Danielle P Porter; Evguenia S Svarovskaia; Véronique Albanèse; Kristina Dietert; Michael Mülleder; Vadim Farztdinov; Benedikt Obermayer; Sandra-Maria Wienhold; Sandro Andreotti; Thomas Höfler; Birgit Sawitzki; Christian Drosten; Leif Erik Sander; Norbert Suttorp; Markus Ralser; Dieter Beule; Achim Dieter Gruber; Christine Goffinet; Markus Landthaler; Jakob Trimpert; Martin Witzenrath

    doi:10.1101/2020.12.19.423600 Date: 2020-12-19 Source: bioRxiv

    Remdesivir (RDV) exhibits potent antiviral activity against SARS-CoV-2 and is currently the only drug approved for the treatment of COVID-19 MESHD. However, little is currently known about the potential for pre-existing resistance to RDV and the possibility of SARS-CoV-2 genetic diversification that might impact RDV efficacy as the virus continue to spread globally. In this study, > 90,000 SARS-CoV-2 sequences from globally circulating clinical isolates and >300 from mink isolates collected through early September 2020 were analyzed for genetic diversity in the RNA replication complex (nsp7, nsp8, nsp10, nsp12, nsp13, and nsp14) with a focus on the RNA-dependent RNA polymerase PROTEIN (nsp12), the molecular target of RDV. Overall, low genetic variation was observed with only 12 amino acid substitutions present in the entire RNA replication complex in [≥]0.5% of analyzed sequences with the highest overall frequency (82.2%) observed for nsp12 P323L that consistently increased over time. Low sequence variation in the RNA replication complex was also observed among the mink isolates. Importantly, the coronavirus Nsp12 mutations previously selected in vitro in the presence of RDV were identified in only 2 isolates (0.002%) within all the analyzed sequences. In addition, among the sequence variants observed in [≥]0.5% clinical isolates, including P323L, none were located near the established polymerase active site or sites critical for the RDV mechanism of inhibition. In summary, the low diversity and high genetic stability of the RNA replication complex observed over time predicts a minimal global risk of pre-existing SARS-CoV-2 resistance to RDV.

    A recombinant fragment of Human surfactant protein D HGNC binds Spike protein PROTEIN and inhibits infectivity and replication of SARS-CoV-2 in clinical samples

    Authors: Taruna Madan; Barnali Biswas; Praveen Varghese; Rambhadur Subedi; Hrishikesh Pandit; Susan Idicula-Thomas; Indra Kundu; Sheetalnath Babasaheb Rooge; Reshu Aggarwal; Dinesh Tripathi; Savneet Kaur; Ekta Gupta; Sanjeev Gupta

    doi:10.1101/2020.12.18.423415 Date: 2020-12-18 Source: bioRxiv

    Rationale COVID-19 MESHD is an acute infectious disease MESHD caused by the Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2). Human surfactant protein D HGNC ( SP-D HGNC) is known to interact with spike protein PROTEIN of SARS-CoV, but its immune-surveillance against SARS-CoV-2 is not known. ObjectiveThis study aimed to examine the potential of a recombinant fragment of human SP-D HGNC (rfhSP-D) as an inhibitor of replication and infection of SARS-CoV-2 MESHD. MethodsrfhSP-D interaction with spike protein PROTEIN of SARS-CoV-2 and hACE-2 receptor was predicted via docking analysis. The inhibition of interaction between spike protein PROTEIN and ACE-2 HGNC by rfhSP-D was confirmed using direct and indirect ELISA. The effect of rfhSP-D on replication and infectivity of SARS-CoV-2 from clinical samples was studied by measuring the expression of RdRp PROTEIN gene of the virus using qPCR. Measurements and Main ResultsIn-silico interaction studies indicated that three amino acid residues in the RBD of spike of SARS-CoV-2 PROTEIN were commonly involved in interacting with rfhSP-D and ACE-2 HGNC. Studies using clinical samples of SARS-CoV-2 positive cases (asymptomatic, n=7 and symptomatic, n=8 and negative controls n=15) demonstrated that treatment with 5M rfhSP-D inhibited viral replication by ~5.5 fold and was more efficient than Remdesivir (100 M). Approximately, a 2-fold reduction in viral infectivity was also observed after treatment with 5M rfhSP-D. ConclusionsThese results conclusively demonstrate that the calcium independent rfhSP-D mediated inhibition of binding between the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike PROTEIN protein and human ACE-2 HGNC, its host cell receptor, and a significant reduction in SARS-CoV-2 infection MESHD and replication in-vitro.

    Remdesivir is a delayed translocation inhibitor of SARS CoV-2 replication in vitro

    Authors: Jack PK Bravo; Tyler L Dangerfield; David W Taylor; Kenneth A Johnson

    doi:10.1101/2020.12.14.422718 Date: 2020-12-16 Source: bioRxiv

    Remdesivir is a nucleoside analog approved by the FDA for treatment of COVID-19 MESHD. Here, we present a 3.9-[A]-resolution cryoEM reconstruction of a remdesivir-stalled RNA-dependent RNA polymerase PROTEIN complex, revealing full incorporation of three copies of remdesivir monophosphate (RMP) and a partially incorporated fourth RMP in the active site. The structure reveals that RMP blocks RNA translocation after incorporation of three bases following RMP, resulting in delayed chain termination, which can guide the rational design of improved antiviral drugs.

    Computational Analysis of Dynamic Allostery and Control in the three SARS-CoV- 2 non-structural proteins PROTEIN

    Authors: Igors Dubanevics; Charles Heaton; Carlos Riechmann; Tom C B McLeish; Theresa A Ramelot; Thomas B. Acton; Elena Moreno; Thomas Kehrer; Catherine A. Royer; Adolfo Garcia-Sastre; Robert M Krug; Gaetano T. Montelione

    doi:10.1101/2020.12.12.422477 Date: 2020-12-14 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic MESHD, has no vaccine or antiviral drugs available to the public, at the time of writing. The virus non-structural proteins are promising drug targets because of their vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which covalently and competitively bind the active site of the non-structural proteins, but little has been done to address regions other than the active site, i.e. for non-competitive inhibition. Here we extend previous work on the SARS-CoV-2 Mpro PROTEIN ( nsp5 HGNC) to three other SARS-CoV-2 proteins: host shutoff factor PROTEIN ( nsp1 HGNC), papain-like protease PROTEIN ( nsp3 HGNC, also known as PLpro PROTEIN) and RNA-dependent RNA-polymerase PROTEIN (nsp12, also known as RdRp) in complex PROTEIN with nsp7 and nsp8 cofactors. Using open-source software (DDPT) to construct Elastic Network Models (ENM) of the chosen proteins we analyse their fluctuation dynamics and thermodynamics, as well as using this protein family to study convergence and robustness of the ENM. Exhaustive 2-point mutational scans of the ENM and their effect on fluctuation free energies suggest several new candidate regions, distant from the active site, for control of the proteins function, which may assist the drug development based on the current small molecule binding screens. The results also provide new insights, including non-additive effects of double-mutation or inhibition, into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure.

    Generation of a SARS-CoV-2 Replicon as a Model System to Dissect Virus Replication and Antiviral Inhibition

    Authors: Xi He; Shuo Quan; Min Xu; Silveria Rodriguez; Shih Lin Goh; Jiajie Wei; Arthur Fridman; Kenneth A Koeplinger; Steve S Carroll; Jay A Grobler; Amy S Espeseth; David B Olsen; Daria J Hazuda; Dai Wang; Ilya Levental; Florian Douam; Robert F. Padera; Bruce D. Levy; Clifford P. Brangwynne

    doi:10.1101/2020.12.12.422532 Date: 2020-12-13 Source: bioRxiv

    SARS-CoV-2 research and antiviral discovery are hampered by the lack of a cell-based virus replication system that can be readily adopted without biosafety level 3 (BSL-3) restrictions. Here, the construction of a non-infectious SARS-CoV-2 reporter replicon and its application in deciphering viral replication mechanisms and evaluating SARS-CoV-2 inhibitors are presented. The replicon genome is replication competent but does not produce progeny virions. Its replication can be inhibited by RdRp PROTEIN mutations or by known SARS-CoV-2 antiviral compounds. Using this system, a high-throughput antiviral assay has also been developed. Significant differences in potencies of several SARS-CoV-2 inhibitors in different cell lines were observed, which highlights the challenges of discovering antivirals capable of inhibiting viral replication in vivo and the importance of testing compounds in multiple cell culture models. The generation of a SARS-CoV-2 replicon provides a powerful platform to expand the global research effort to combat COVID-19 MESHD.

    Antibody landscape against SARS-CoV-2 proteome revealed significant differences between non-structural/ accessory proteins and structural proteins

    Authors: Yang Li; Zhaowei Xu; Qing Lei; Danyun Lai; Hongyan Hou; Hewei Jiang; yunxiao Zheng; Xuening Wang; Jiaoxiang Wu; Mingliang Ma; Bo Zhang; Hong Chen; Caizheng Yu; Junbiao Xue; Nainang Zhang; Huan Qi; Shujuan Guo; Yandi Zhang; Xiaosong Lin; Zongjie Yao; Huiming Sheng; Ziyong Sun; Feng Wang; Xionglin Fan; Sheng-ce Tao

    doi:10.1101/2020.12.08.20246314 Date: 2020-12-11 Source: medRxiv

    The immunogenicity of SARS-CoV-2 proteome is largely unknown, especially for non-structural proteins and accessory proteins. Here we collected 2,360 COVID-19 MESHD sera and 601 control sera. We analyzed these sera on a protein microarray with 20 proteins of SARS-CoV-2, built an antibody response landscape for IgG and IgM. We found that non-structural proteins and accessory proteins NSP1 HGNC, NSP7 PROTEIN, NSP8 PROTEIN, RdRp PROTEIN, ORF3b PROTEIN and ORF9b PROTEIN elicit prevalent IgG responses. The IgG patterns and dynamic of non-structural/ accessory proteins are different from that of S and N protein PROTEIN. The IgG responses against these 6 proteins are associated with disease severity and clinical outcome and declined sharply about 20 days after symptom onset. In non-survivors, sharp decrease of IgG antibodies against S1 and N HGNC N protein PROTEIN before death was observed. The global antibody responses to non-structural/ accessory proteins revealed here may facilitate deeper understanding of SARS-CoV-2 immunology. HighlightsO_LIAn antibody response landscape against SARS-CoV-2 proteome was constructed C_LIO_LINon-structural/accessory proteins elicit prevalent antibody responses but likely through a different mechanism to that of structural proteins C_LIO_LIIgG antibodies against non-structural/accessory proteins are more associated with disease severity and clinical outcome C_LIO_LIFor non-survivors, the levels of IgG antibodies against S1 and N HGNC decline significantly before death C_LI

    A COVID-19 MESHD Drug Repurposing Strategy Through Quantitative Homological Similarities by using a Topological Data Analysis Based Formalism

    Authors: Raul Pérez-Moraga; Jaume Forés-Martos; Beatriz Suay; Jean-Louis Duval; Antonio Falcó; Joan Climent

    id:10.20944/preprints202012.0281.v1 Date: 2020-12-11 Source: Preprints.org

    Since its emergence in March 2020, the SARS-CoV-2 global pandemic has produced more than 65 million cases and one point five million deaths worldwide. Despite the enormous efforts carried out by the scientific community, no effective treatments have been developed to date. We created a novel computational pipeline aimed to speed up the process of repurposable candidate drug identification. Compared with current drug repurposing methodologies, our strategy is centered on filtering the best candidate among all selected targets focused on the introduction of a mathematical formalism motivated by recent advances in the fields of algebraic topology and topological data analysis (TDA). This formalism allows us to compare three-dimensional protein structures. Its use in conjunction with two in silico validation strategies (molecular docking and transcriptomic analyses) allowed us to identify a set of potential drug repurposing candidates targeting three viral proteins (3CL viral protease, NSP15 PROTEIN endoribonuclease, and NSP12 PROTEIN RNA-dependent RNA polymerase PROTEIN), which included rutin, dexamethasone, and vemurafenib among others. To our knowledge, it is the first time that a TDA based strategy has been used to compare a massive amount of protein structures with the final objective of performing drug repurposing

    Tea flavonoids blocking multiple SARS-CoV-2 protein targets judged from molecular docking

    Authors: Lufei Wang; Siyao Sang; Mingjie Su; Simin Wang; Hui Li

    doi:10.21203/rs.3.rs-122589/v1 Date: 2020-12-05 Source: ResearchSquare

    Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2) has caused Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2) pandemic. Flavonoids derived Chinese patent medicines has outstanding curative effects for the improvement and treatment of COVID-19 MESHD. There are numerous studies suggesting that flavonoids-rich tea have antiviral effects. However, bioactive compounds from tea flavonoids with anti- COVID-19 MESHD effect, and the potential molecular mechanisms are unclear. In this study, we performed a molecular docking of 468 tea flavonoids and its derivatives with main protease PROTEIN ( Mpro PROTEIN), angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC), RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN), compared with the positive control drugs of each target. The results suggested that ACE2 HGNC and RdRp PROTEIN are the main targets inhibited by tea flavonoids.Q3G Isovitexin, and TF would be considered as the potential candidate compounds of RdRp PROTEIN and ACE2 HGNC. Our study provides a theoretical basis for further drug design of anti- COVID-19 MESHD.

    Consistent and High-Frequency Identification of an Intra-Sample Genetic Variant of SARS-CoV-2 with Elevated Fusogenic Properties

    Authors: Lynda Rocheleau; Geneviève Laroche; Kathy Fu; Marceline Côté; Patrick M Giguère; Marc-André Langlois; Martin Pelchat; Peter Mohr; Remo Gamboni; Thanos D. Halazonetis; Kai-Thomas Schneider; Kristian Daniel Ralph Roth; Philipp Kuhn; Peggy Riese; Dorina Schäckermann; Janin Korn; Allan Koch; Susanne Zock-Emmenthal; Marlies Becker; Margitta Scholz; Gustavo Marçal Schmidt Garcia Moreira; Esther Veronika Wenzel; Giulio Russo; Hendrikus S.P. Garritsen; Sebastian Casu; Andreas Gerstner; Günter Roth; Andreas Hermann; Thomas Schirrmann; Stefan Dübel; André Frenzel; Joop Van den Heuvel; Luka Cicin-Sain; Maren Schubert; Michael Hust

    doi:10.1101/2020.12.03.409714 Date: 2020-12-03 Source: bioRxiv

    The severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) has a genome comprised of a ~30K nucleotides non-segmented, positive single-stranded RNA. Although its RNA-dependent RNA polymerase PROTEIN exhibits exonuclease proofreading activity, viral sequence diversity can be induced by replication errors and host factors. These variations can be observed in the population of viral sequences isolated from infected host cells and are not necessarily reflected in the genome of transmitted founder viruses. We profiled intra-sample genetic diversity of SARS-CoV-2 variants using 15,289 high-throughput sequencing datasets from infected individuals and infected cell lines. Most of the genetic variations observed, including C->U and G->U, were consistent with errors due to heat-induced DNA damage during sample processing, and/or sequencing protocols. Despite high mutational background, we confidently identified intra-variable positions recurrent in the samples analyzed, including several positions at the end of the gene encoding the viral S protein PROTEIN. Notably, most of the samples possesses a C->A missense mutation resulting in the S protein PROTEIN lacking the last 20 amino acids (S{Delta}20). Here we demonstrate that S{Delta}20 exhibits increased cell-to-cell fusion and syncytia formations MESHD. Our findings are suggestive of the consistent emergence of high-frequency viral quasispecies that are not horizontally transmitted but involved in intra-host infection MESHD and spread. Author summaryThe severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) and its associated disease, COVID-19 MESHD, has caused significant worldwide mortality and unprecedented economic burden. Here we studied the intra-host genetic diversity of SARS-CoV-2 genomes and identified a high-frequency and recurrent non-sense mutation yielding a truncated form of the viral spike protein PROTEIN, in both human COVID-19 MESHD samples and in cell culture experiments. Through the use of a functional assay, we observed that this truncated spike protein PROTEIN displays an elevated fusogenic potential and forms syncytia. Given the high frequency at which this mutation independently arises across various samples, it can be hypothesized that this deletion mutation provides a selective advantage to viral replication and may also have a role in pathogenesis in humans.

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SARS-CoV-2 Proteins


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