Corpus overview


MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP13 (13)

ProteinN (6)

ORF3a (6)

NSP3 (5)

NSP2 (4)


SARS-CoV-2 Proteins
    displaying 1 - 10 records in total 13
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    Structure, Mechanism and Crystallographic fragment screening of the SARS-CoV-2 NSP13 PROTEIN helicase

    Authors: Joseph A Newman; Alice Douangamath; Setayesh Yazdani; Yuliana Yosaatmadja; Anthony Aimon; Jose Brandao-Neto; Louise Dunnett; Tyler Gorrie-Stone; Rachael Skyner; Daren Fearon; Matthieu Schapira; Frank von Delft; Opher Gileadi

    doi:10.1101/2021.03.15.435326 Date: 2021-03-15 Source: bioRxiv

    The global COVID-19 pandemic MESHD is caused by the SARS-CoV-2 virus MESHD and has infected over 100 million and caused over 2 million fatalities worldwide at the point of writing. There is currently a lack of effective drugs to treat people infected MESHD with SARS-CoV-2. The SARS-CoV- 2 Non-structural protein PROTEIN 13 ( NSP13 PROTEIN) is a superfamily1B helicase that has been identified as a possible target for anti-viral drugs due to its high sequence conservation and essential role in viral replication. In this study we present crystal structures of SARS-CoV-2 NSP13 PROTEIN solved in the APO form and in the presence of both phosphate and the non-hydrolysable ATP analogue (AMP-PNP). Comparisons of these structures reveal details of global and local conformational changes that are induced by nucleotide binding and hydrolysis and provide insights into the helicase mechanism and possible modes of inhibition. Structural analysis reveals two pockets on NSP13 PROTEIN that are classified as "druggable" and include one of the most conserved sites in the entire SARS-CoV-2 proteome. To identify possible starting points for anti-viral drug development we have performed a crystallographic fragment screen against SARS-CoV-2 NSP13 PROTEIN helicase. The fragment screen reveals 65 fragment hits across 52 datasets, with hot spots in pockets predicted to be of functional importance, including the druggable nucleotide and nucleic acid binding sites, opening the way to structure guided development of novel antiviral agents.

    Detection of the new SARS-CoV-2 variant B.1.526 with the Spike E484K mutation in South America

    Authors: Juan Fernández Cadena; Mindy Muñoz; Gabriel Morey León; Rubén Armas-González; Darlyn Amaya Márquez; Katheryn Sacheri Viteri; Paúl Cárdenas & USFQ-COVID Consortium; Fernando Valiente-Echeverría; Ricardo Soto Rifo; Derly Andrade Molina

    doi:10.21203/ Date: 2021-02-17 Source: ResearchSquare

    Here, we report two sequences of the new SARS-CoV-2 variant recently detected and designed as B.1.526. This variant carries the immune escape-associated mutation E484K and additional mutations in the S, N, NSP2 PROTEIN NSP2 HGNC, NSP3 HGNC NSP3 PROTEIN, NSP4 PROTEIN NSP4 HGNC, NSP6 PROTEIN, NSP8 PROTEIN, NSP12 PROTEIN and NSP13 PROTEIN genes. Viral sequences were obtained from an individual traveling from the US to Equator with a negative RT-PCR and from one of his closest contacts that became infected. These cases should be considered an alert for the potential circulation of a new variant of concern with the E484K mutation in South America

    Identification of novel candidate CD8 HGNC+ T cell epitopes of the SARS-CoV2 with homology to other seasonal coronaviruses

    Authors: Pradeep Pushpakumara; Deshan Madusanka; Saubhagyagya Danasekara; Chandima Jeewandara; Graham Ogg; Gathsaurie Neelika Malavige

    doi:10.21203/ Date: 2021-02-10 Source: ResearchSquare

    Background Individuals who have not been exposed to the SARS-CoV2 virus have been shown to have T cells that respond to the virus, possibly due to the presence of cross-reactive T cell responses to other seasonal human coronaviruses (HCoVs). Such cross-reactive T cell immunity may lead to immunopathology or protection.Results To understand the influence of such cross-reactive T cell responses, we used IEDB (Immune epitope database) and NetMHCpan (ver. 4.1) to identify candidate CD8 HGNC + T cell epitopes, restricted through HLA-A and B alleles, which are seen in a frequency of > 10% in the Sri Lankan population. Conservation analysis was carried out for these candidate epitopes with the HCoVs, OC43, HKU1, NL63 and with the current circulating different variants of SARS-CoV2. 12/18 the candidate CD8 HGNC + T cell epitopes (binding score of ≥ 0.90), which had a high degree of homology (> 75%) with the other three HCoVs were within the NSP12 PROTEIN and NSP13 PROTEIN proteins. They were predicted to be restricted through HLA-A HGNC*2402, HLA-A HGNC*201, HLA-A HGNC*206 and HLA-B HGNC alleles B*3501. 31 candidate CD8 HGNC + T cell epitopes that were specific to SARS-CoV2 virus (< 25% homology with other HCoVs) were predominantly identified within the structural proteins (spike PROTEIN, envelop, membrane and nucleocapsid) and the NSP1 HGNC, NSP2 PROTEIN NSP2 HGNC and NSP3 PROTEIN NSP3 HGNC. They were predominantly restricted through HLA-B HGNC*3501 (6/31), HLA-B HGNC*4001 (6/31), HLA-B HGNC*4403(7/31) and HLA-A HGNC*2402 (8/31). The candidate CD8 HGNC + T cell epitopes that were homologous or were specific, with a binding score of ≥ 0.90, were found to be highly conserved within the SARS-CoV2 variants identified so far.Conclusions It would be crucial to understand T cell responses that associate with protection and the differences in the functionality and phenotype of epitope specific T cell responses, presented through different HLA alleles common in different geographical groups in order to understand disease pathogenesis.

    BCG vaccine derived peptides induce SARS-CoV-2 T cell cross-reactivity

    Authors: Peter J Eggenhuizen; Boaz H Ng; Janet Chang; Ashleigh L Fell; Wey Y Wong; Poh-yi Gan; Stephen R Holdsworth; Joshua D Ooi

    doi:10.1101/2020.11.21.20236018 Date: 2020-11-23 Source: medRxiv

    Epidemiological studies suggest that the Bacillus Calmette-Guerin (BCG) vaccine may have protective effects against coronavirus disease 2019 MESHD ( COVID-19 MESHD); and, there are now more than 15 ongoing clinical trials seeking to determine if BCG vaccination can prevent or reduce the severity of COVID-19 MESHD (1). However, the mechanism by which BCG vaccination can induce a severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) specific T cell response is unknown. Here, in silico, we identify 8 BCG derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 MESHD NSP3 PROTEIN NSP3 HGNC or NSP13 PROTEIN derived peptides. Using an in vitro co-culture system, we show that human CD4 HGNC+ and CD8 HGNC+ T cells primed with a BCG derived peptide developed enhanced reactivity to its corresponding SARS-CoV-2 derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2 derived peptides. These findings provide a mechanistic basis for the epidemiologic observation that BCG vaccination confers protection from COVID-19 MESHD; and supports the use of BCG vaccination to induce cross-reactive SARS-CoV-2 specific T cell responses.

    Potential Achilles heels of SARS-CoV-2 displayed by the base order-dependent component of RNA folding energy

    Authors: Chiyu Zhang; Jana De Vrieze; Angela Choi; Raveen Rathnasinghe; Gabriel Laghlali; Annemiek Uvyn; Simon Van Herck; Lutz Nuhn; Kim Deswarte; Zifu Zhong; Niek Sanders; Stefan Lienenklaus; Sunil David; Shirin Strohmeier; Fatima Amanat; Florian Krammer; Hamida Hammad; Bart N Lambrecht; Lynda Coughlan; Adolfo Garcia-Sastre; Bruno G De Geest; Michael Schotsaert; Marion Yger; Bertrand Degos; Louise-Laure Mariani; Christophe Bouche; Nathalie Dzierzynski; Bruno Oquendo; Flora Ketz; An-Hung Nguyen; Aurelie Kas; Jean-Yves Delattre; Jean-Christophe Corvol

    doi:10.1101/2020.10.22.343673 Date: 2020-10-23 Source: bioRxiv

    The energetics of the folding of a single-stranded nucleic acid into a stem-loop structure depend on both the composition and order of its bases. Composition tends to reflect genome-wide evolutionary pressures. Order better reflects local pressures. Base order is likely to be conserved when encoding a function critical for survival. The base order-dependent component of the folding energy has shown that a highly conserved region in HIV-1 genomes associates with an RNA structure. This corresponds to a packaging signal that is specifically recognized by the nucleocapsid domain of the Gag polyprotein HGNC. Long viewed as a potential HIV-1 "Achilles heel," the signal can be targeted by a recently described antiviral compound (NSC 260594) or by synthetic oligonucleotides. Thus, a conserved base-order-rich region of HIV-1 may facilitate therapeutic attack. Although SARS-CoV-2 differs in many respects from HIV-1, the same technology displays regions with a high base order-dependent folding energy component, which are also highly conserved. This indicates structural invariance (SI) sustained by natural selection. While the regions are often also protein-encoding (e.g. NSP3 HGNC NSP3 PROTEIN, ORF3a PROTEIN), we suggest that their nucleic acid level functions, such as the ribosomal frameshifting element (FSE) that facilitates differential expression of 1a and 1ab polyproteins, can be considered potential "Achilles heels" for SARS-CoV-2 that should be susceptible to therapies like those envisaged for AIDS MESHD. The region of the FSE scored well, but higher SI scores were obtained in other regions, including those encoding NSP13 PROTEIN and the nucleocapsid (N) protein PROTEIN.

    Mutational analysis and assessment of its impact on proteins of SARS-CoV-2 genomes from India

    Authors: Rezwanuzzaman Laskar; Safdar Ali; Malte C Ebach; David M Williams; Ard Mulders; Ron AM Fouchier; Sander Herfst; Yi Shi; Hong Liu; Lirong Zhang; Lijie Song; Louisa S Chard Dunmall; Jianzeng Dong; Nicholas R Lemoine; Yaohe Wang; Daniel Cordero; Daniela Solano; Gina Durán; Eduardo Segura; Maykel Cerdas; Deibid Umaña; Edwin Moscoso; Ricardo Estrada; Jairo Gutiérrez; Marcos Méndez; Ana Cecilia Castillo; Laura Sánchez; José María Gutiérrez; Cecilia Díaz; Alberto Alape

    doi:10.1101/2020.10.19.345066 Date: 2020-10-19 Source: bioRxiv

    The ongoing global pandemic of SARS-CoV-2 implies a corresponding accumulation of mutations. Herein the mutational status of 611 genomes from India along with their impact on proteins was ascertained. After excluding gaps and ambiguous sequences, a total of 493 variable sites (152 parsimony informative and 341 singleton) were observed. The most prevalent reference nucleotide was C (209) and substituted one was T (293). NSP3 HGNC NSP3 PROTEIN had the highest incidence of 101 sites followed by S protein PROTEIN (74 sites), NSP12b (43 sites) and ORF3a PROTEIN (31 sites). The average number of mutations per sample for males and females was 2.56 and 2.88 respectively suggesting a higher contribution of mutations from females. Non-uniform geographical distribution of mutations implied by Odisha (30 samples, 109 mutations) and Tamil Nadu (31 samples, 40 mutations) suggests that sequences in some regions are mutating faster than others. There were 281 mutations (198 Neutral and 83 Disease) affecting amino acid sequence. NSP13 PROTEIN has a maximum of 14 Disease variants followed by S protein PROTEIN and ORF3a PROTEIN with 13 each. Further, constitution of Disease MESHD mutations in genomes from asymptomatic people was mere 11% but those from deceased patients was over three folds higher at 38% indicating contribution of these mutations to the pathophysiology of the SARS-CoV-2.

    Early induction of SARS-CoV-2 specific T cells associates with rapid viral clearance and mild disease in COVID-19 MESHD patients

    Authors: Anthony T Tan; Martin Linster; Cheewah Tan; Nina Le Bert; Wanni Chia; Kamini Kunasegaran; Yan Zhuang; Christine YL Tham; Adeline Chia; Gavin James Smith; Barnaby Edward Young; Shirin Kalimuddin; Jenny GH Low; David Lye; Lin-Fa Wang; Antonio Bertoletti; Sudipta Majumdar; Gregory A Weiss; Takahiro Ochiya; Charlotte Lanteri; Edward Mitre; Timothy H. Burgess; Christopher C. Broder; Graham Lord; Timothy Felton; Chris Brightling; Ling-Pei Ho; - NIHR Respiratory TRC; - CIRCO; Karen Piper Hanley; Angela Simpson; John R Grainger; Tracy Hussell; Elizabeth R Mann

    doi:10.1101/2020.10.15.341958 Date: 2020-10-16 Source: bioRxiv

    Virus-specific humoral and cellular immunity act synergistically to protect the host from viral infection MESHD. We interrogated the dynamic changes of virological and immunological parameters in 12 patients with symptomatic acute SARS-CoV-2 infection MESHD from disease onset to convalescence or death MESHD. We quantified SARS-CoV-2 viral RNA in the respiratory tract in parallel with antibodies and circulating T cells specific for various structural (NP, M, ORF3a PROTEIN and spike) and non-structural proteins (ORF7/8, NSP7 PROTEIN and NSP13 PROTEIN). We observed that while rapid induction and quantity of humoral responses were associated with increased disease severity, an early induction of SARS-CoV-2 specific T cells was present in patients with mild disease MESHD and accelerated viral clearance. These findings provide further support for a protective role of SARS-CoV-2 specific T cells over antibodies during SARS-CoV-2 infection MESHD with important implications in vaccine design and immune-monitoring.

    A Systemic and Molecular Study of Subcellular Localization of SARS-CoV-2 Proteins

    Authors: Jing Zhang; Ruth Cruz-cosme; Meng-Wei Zhuang; Dongxiao Liu; Yuan Liu; Shaolei Teng; Pei-Hui Wang; Qiyi Tang

    doi:10.1101/2020.08.02.233023 Date: 2020-08-02 Source: bioRxiv

    Coronavirus possesses the largest RNA genome among all the RNA viruses. Its genome encodes about 29 proteins. Most of the viral proteins are non-structural proteins (NSP) except envelop (E), membrane (M), nucleocapsid (N PROTEIN) and Spike (S) proteins PROTEIN that constitute the viral nucleocapsid, envelop and surface. We have recently cloned all the 29 SARS-CoV-2 genes into vectors for their expressions in mammalian cells except NSP11 PROTEIN that has only 14 amino acids (aa). We are able to express all the 28 cloned SARS-CoV-2 genes in human cells to characterize their subcellular distributions. The proteins of SARS-CoV-2 are mostly cytoplasmic but some are both cytoplasmic and nuclear. Those punctate staining proteins were further investigated by immunofluorescent assay (IFA) using specific antibodies or by co-transfection with an organelle marker-expressing plasmid. As a result, we found that NSP15 PROTEIN, ORF6 PROTEIN, M and ORF7a PROTEIN are related to Golgi apparatus, and that ORF7b PROTEIN, ORF8 PROTEIN and ORF10 PROTEIN colocalize with endoplasmic reticulum (ER). Interestingly, ORF3a PROTEIN distributes in cell membrane, early endosome, endosome, late endosome and lysosome, which suggests that ORF3a PROTEIN might help the infected virus to usurp endosome and lysosome for viral use. Furthermore, we revealed that NSP13 PROTEIN colocalized with SC35 HGNC, a protein standing for splicing compartments in the nucleus. Our studies for the first time visualized the subcellular locations of SARS-CoV-2 proteins MESHD and might provide novel insights into the viral proteins biological functions.

    Force-dependent stimulation of RNA unwinding by SARS-CoV-2 nsp13 helicase

    Authors: Keith J Mickolajczyk; Patrick M M Shelton; Michael Grasso; Xiaocong Cao; Sara R Warrington; Amol Aher; Shixin Liu; Tarun M Kapoor

    doi:10.1101/2020.07.31.231274 Date: 2020-07-31 Source: bioRxiv

    The superfamily-1 helicase non-structural protein 13 PROTEIN (nsp13) is required for SARS-CoV-2 replication, making it an important antiviral therapeutic target. The mechanism and regulation of nsp13 has not been explored at the single-molecule level. Specifically, force-dependent unwinding experiments have yet to be performed for any coronavirus helicase. Here, using optical tweezers, we find that nsp13 unwinding frequency, processivity, and velocity increase substantially when a destabilizing force is applied to the dsRNA, suggesting a passive unwinding mechanism. These results, along with bulk assays, depict nsp13 as an intrinsically weak helicase that can be potently activated by picoNewton forces. Such force-dependent behavior contrasts the known behavior of other viral monomeric helicases, drawing stronger parallels to ring-shaped helicases. Our findings suggest that mechanoregulation, which may be provided by a directly bound RNA-dependent RNA polymerase PROTEIN, enables on-demand helicase activity on the relevant polynucleotide substrate during viral replication.

    New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release

    Authors: Tre Tomaszewski; Ryan S DeVries; Mengyi Dong; Gitanshu Bhatia; Miles D Norsworthy; Xuying Zheng; Gustavo Caetano-Anolles

    doi:10.1101/2020.07.31.231472 Date: 2020-07-31 Source: bioRxiv

    The massive worldwide spread of the SARS-CoV-2 virus is fueling the COVID-19 MESHD COVID-19 MESHD pandemic. Since the first whole-genome sequence was published in January 2020, a growing database of tens of thousands of viral genomes has been constructed. This offers opportunities to study pathways of molecular change in the expanding viral population that can help identify molecular culprits of virulence and virus spread. Here we investigate the genomic accumulation of mutations at various time points of the early pandemic to identify changes in mutationally highly active genomic regions that are occurring worldwide. We used the Wuhan NC_045512.2 sequence as a reference and sampled 15,342 indexed sequences from GISAID, translating them into proteins and grouping them by month of deposition. The per-position amino acid frequencies and Shannon entropies of the coding sequences were calculated for each month, and a map of intrinsic disorder MESHD regions and binding sites was generated. The analysis revealed dominant variants, most of which were located in loop regions and on the surface of the proteins. Mutation entropy decreased between March and April of 2020 after steady increases at several sites, including the D614G mutation site of the spike (S) protein PROTEIN that was previously found associated with higher case fatality rates and at sites of the NSP 12 polymerase and the NSP13 PROTEIN helicase proteins. Notable expanding mutations include R203K and G204R of the nucleocapsid (N) protein PROTEIN inter-domain linker region and G251V of the viroporin encoded by ORF3a PROTEIN between March and April. The regions spanning these mutations exhibited significant intrinsic disorder MESHD, which was enhanced and decreased by the N-protein PROTEIN and viroporin 3a protein mutations, respectively. These results predict an ongoing mutational shift from the spike and replication complex to other regions, especially to encoded molecules known to represent major {beta}-interferon antagonists. The study provides valuable information for therapeutics and vaccine design, as well as insight into mutation tendencies that could facilitate preventive control.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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