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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (2072)

ProteinN (185)

NSP5 (63)

ProteinS1 (55)

ComplexRdRp (52)


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SARS-CoV-2 Proteins
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    A repurposed drug screen identifies compounds that inhibit the binding of the COVID-19 MESHD spike protein PROTEIN to ACE2

    Authors: Kaleb B Tsegay; Christiana M Adeyemi; Edward P Gniffke; John K Walker; Stephen E.P. Smith

    doi:10.1101/2021.04.08.439071 Date: 2021-04-08 Source: bioRxiv

    Repurposed drugs that block the interaction between the SARS-CoV-2 spike PROTEIN protein and its receptor ACE2 HGNC could offer a rapid route to novel COVID-19 MESHD treatments or prophylactics. Here, we screened 2701 compounds from a commercial library of drugs approved by international regulatory agencies for their ability to inhibit the binding of recombinant, trimeric SARS-CoV-2 spike PROTEIN protein to recombinant human ACE2 HGNC. We identified 56 compounds that inhibited binding by <90%, measured the EC50 of binding inhibition, and computationally modeled the docking of the best inhibitors to both Spike and ACE2 HGNC. These results highlight an effective screening approach to identify compounds capable of disrupting the Spike- ACE2 HGNC interaction as well as identifying several potential inhibitors that could serve as templates for future drug discovery efforts.

    Polymersomes decorated with SARS-CoV-2 spike PROTEIN protein receptor binding domain elicit robust humoral and cellular immunity

    Authors: Lisa R Volpatti; Rachel P Wallace; Shijie Cao; Michal Raczy; Ruyi Wang; Laura T Gray; Aaron T Alpar; Priscilla S Briquez; Nikolaos Mitrousis; Tiffany M Marchell; Maria Stella Sasso; Mindy Nguyen; Aslan Mansurov; Erica Budina; Ani Solanki; Elyse A Watkins; Mathew R Schnorenberg; Andrew C Tremain; Joseph W Reda; Vlad Nicolaescu; Kevin Furlong; Steve Dvorkin; Shann S Yu; Balaji Manicassamy; James L LaBelle; Matthew V Tirrell; Glenn Randall; Marcin Kwissa; Melody Swartz; Jeffrey Hubbell

    doi:10.1101/2021.04.08.438884 Date: 2021-04-08 Source: bioRxiv

    A diverse portfolio of SARS-CoV-2 vaccine candidates is needed to combat the evolving COVID-19 pandemic MESHD. Here, we developed a subunit nanovaccine by conjugating SARS-CoV-2 Spike PROTEIN protein receptor binding domain (RBD) to the surface of oxidation-sensitive polymersomes. We evaluated the humoral and cellular responses of mice immunized with these surface-decorated polymersomes (RBDsurf) compared to RBD-encapsulated polymersomes (RBDencap) and unformulated RBD (RBDfree), using monophosphoryl lipid A-encapsulated polymersomes (MPLA PS) as an adjuvant. While all three groups produced high titers of RBD-specific IgG, only RBDsurf elicited a neutralizing antibody response to SARS-CoV-2 comparable to that of human convalescent plasma. Moreover, RBDsurf was the only group to significantly increase the proportion of RBD-specific germinal center B cells in the vaccination-site draining lymph nodes. Both RBDsurf and RBDencap drove similarly robust CD4+ and CD8+ T cell responses that produced multiple Th1-type cytokines. We conclude that multivalent surface display of Spike RBD on polymersomes promotes a potent neutralizing antibody response to SARS-CoV-2, while both antigen formulations promote robust T cell immunity.

    Functional evaluation of proteolytic activation for the SARS-CoV-2 variant B.1.1.7: role of the P681H mutation

    Authors: Bailey Lubinski; Tiffany Tang; Susan Daniel; Javier A. Jaimes; Gary Whittaker

    doi:10.1101/2021.04.06.438731 Date: 2021-04-08 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) is the agent behind the current COVID-19 pandemic MESHD having emerged in Wuhan China in late 2019 from a yet to be determined animal reservoir. SARS-CoV-2 B.1.1.7, a variant identified in the UK in late 2020, contains a higher than typical level of point mutants across its genome, including P681H in the spike S1/S2 cleavage site. Here, we performed assays using fluorogenic peptides mimicking the S1/S2 sequence from Wuhan-Hu1 and B.1.1.7 and observed no definitive difference in furin cleavage between Wuhan-Hu1 and B.1.1.7 in vitro. We performed functional assays using pseudo-typed particles harboring SARS-CoV-2 spike PROTEIN proteins and observed no significant differences between Wuhan-Hu1, Wuhan-Hu1 P681H or B.1.1.7 spike-carrying pseudo-typed particles in VeroE6 or Vero-TMPRSS2 cells, despite the spikes containing P681H being more efficiently cleaved. Likewise, we or show no differences in cell-cell fusion assays using the spike P681H-expressing cells. Our findings suggest that while the introduction of P681H in the SARS-CoV-2 B.1.1.7 variant may increase spike cleavage by furin-like proteases, this does not significantly impact viral entry or cell-cell spread. We consider that other factors are at play to account for the increased in transmission and disease severity attributed to this variant of concern (VOC).

    Genomic Sequencing of SARS-COV-2 in Rwanda: evolution and regional dynamics

    Authors: Yvan Butera; Enatha Mukantwari; Maria Artesi; Jeanne D'Arc Umuringa; Aine Niamh O'Toole; Verity Hill; Stefan Rooke; Samuel Leandro Hong; Simon Dellicour; Onesphore Majyambere; Sebastien Bontems; Bouchra Boujemla; Josh Quick; Paola Cristina Resende; Nicholas James Loman; Esperance Umumararungu; Alice Kabanda; Marylin Milumbu Murindahabi; Patrick Tuyisenge; Misbah Gashegu; Jean Paul Rwabihama; Reuben Sindayiheba; Djordje Gikic; Jacob Souopgui; Wilfred Ndifon; Robert Rutayisire; Swaibu Gatare; Tharcisse Mpunga; Daniel Ngamije; Vincent Bours; Andrew Rambaut; Sabin Nsanzimana; Guy Baele; Keith Durkin; Leon Mutesa; Nadine Rujeni

    doi:10.1101/2021.04.02.21254839 Date: 2021-04-07 Source: medRxiv

    The severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), responsible for coronavirus disease MESHD 19 ( COVID-19 MESHD), is a single-stranded positive-sense ribonucleic acid (RNA) virus that typically undergoes one to two single nucleotide mutations per month. COVID-19 MESHD continues to spread globally, with case fatality and test positivity rates often linked to locally circulating strains of SARS-CoV-2. Furthermore, mutations in this virus, in particular those occurring in the spike protein PROTEIN (involved in the virus binding to the host epithelial cells) have potential implications in current vaccination efforts. In Rwanda, more than twenty thousand cases have been confirmed as of March 14th 2021, with a case fatality rate of 1.4% and test positivity rate of 2.3% while the recovery rate is at 91.9%. Rwanda started its genomic surveillance efforts, taking advantage of pre-existing research projects and partnerships, to ensure early detection of SARS-CoV-2 variants and to potentially contain the spread of variants of concern (VOC). As a result of this initiative, we here present 203 SARS-CoV-2 whole genome sequences analyzed from strains circulating in the country from May 2020 to February 2021. In particular, we report a shift in variant distribution towards the newly emerging sub-lineage A.23.1 that is currently dominating. Furthermore, we report the detection of the first Rwandan cases of the VOCs, B.1.1.7 and B.1.351, among incoming travelers tested at Kigali International Airport. We also discuss the potential impact of COVID-19 MESHD control measures established in the country to control the spread of the virus. To assess the importance of viral introductions from neighboring countries and local transmission, we exploit available individual travel history metadata to inform spatio-temporal phylogeographic inference, enabling us to take into account infections from unsampled locations during the time frame of interest. We uncover an important role of neighboring countries in seeding introductions into Rwanda, including those from which no genomic sequences are currently available or that no longer report positive cases. Our results point to the importance of systematically screening all incoming travelers, regardless of the origin of their travels as well as regional considerations for durable response to COVID-19 MESHD.

    mRNA vaccination compared to infection elicits an IgG-predominant response with greater SARS-CoV-2 specificity and similar decrease in variant spike recognition

    Authors: Katharina Roeltgen; Sandra C.A. Nielsen; Prabhu S Arunachalam; Fan Yang; Ramona A. Hoh; Oliver F. Wirz; Alexandra S Lee; Fei Gao; Vamsee Mallajosyula; Chunfeng Li; Emily Haraguchi; Massa J Shoura; James L Wilbur; Jacob N. Wohlstadter; Mark M. Davis; Benjamin A. Pinsky; George B. Sigal; Bali Pulendran; Kari C. Nadeau; Scott D. Boyd

    doi:10.1101/2021.04.05.21254952 Date: 2021-04-07 Source: medRxiv

    During the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) pandemic, new vaccine strategies including lipid nanoparticle delivery of antigen encoding RNA have been deployed globally. The BioNTech/Pfizer mRNA vaccine BNT162b2 encoding SARS-CoV-2 spike PROTEIN protein shows 95% efficacy in preventing disease, but it is unclear how the antibody responses to vaccination differ from those generated by infection. Here we compare the magnitude and breadth of antibodies targeting SARS-CoV-2, SARS-CoV-2 variants of concern, and endemic coronaviruses, in vaccinees and infected MESHD patients. We find that vaccination differs from infection in the dominance of IgG over IgM and IgA responses, with IgG reaching levels similar to those of severely ill COVID-19 MESHD patients and shows decreased breadth of the antibody response targeting endemic coronaviruses. Viral variants of concern from B.1.1.7 to P.1 to B.1.351 form a remarkably consistent hierarchy of progressively decreasing antibody recognition by both vaccinees and infected MESHD patients exposed to Wuhan-Hu-1 antigens.

    Single Prime hAd5 Spike (S) + Nucleocapsid (N PROTEIN) Dual Antigen Vaccination of Healthy Volunteers Induces a Ten-Fold Increase in Mean S- and N- T-Cell Responses Equivalent to T-Cell Responses from Patients Previously Infected with SARS-CoV-2

    Authors: Pete Sieling; Thomas King; Raymond Wong; Andy Nguyen; Kamil Wnuk; Elizabeth R Gabitzsch; Adrian Rice; Helty Adisetiyo; Melanie Hermreck; Mohit Verma; Lise Zakin; Annie Shin; Brett Morimoto; Wendy Higashide; Kyle Dinkins; Joseph Balint; Victor Peykov; Justin Taft; Roosheel Patel; Sofija Buta; Marta Martin-Fernandez; Dusan Bogunovic; Patricia Spilman; Lennie Sender; Sandeep Reddy; Philip Robinson; Shahrooz Rabizadeh; Kayvan Niazi; Patrick Soon-Shiong

    doi:10.1101/2021.04.05.21254940 Date: 2021-04-07 Source: medRxiv

    In response to the need for a safe, efficacious vaccine that provides broad immune protection against SARS-CoV-2 infection MESHD, we have developed a dual-antigen COVID-19 MESHD vaccine. The vaccine delivers both the viral spike (S) protein PROTEIN modified to increase cell-surface expression (S-Fusion) and the viral nucleocapsid (N) protein PROTEIN with an Enhanced T-cell Stimulation Domain (N-ETSD) to enhance MHC class I and II presentation and T-cell responses. The vaccine antigens are delivered using a human adenovirus serotype 5 (hAd5) platform with E1, E2b, and E3 regions deleted that has been shown in previous cancer MESHD vaccine studies to be effective in the presence of pre-existing hAd5 immunity. Here, we demonstrate the hAd5 S-Fusion + N-ETSD (hAd5 S + N) vaccine antigens when expressed by dendritic cells (DCs) of previously SARS-CoV-2-infected MESHD patients elicit Th1 HGNC dominant activation of autologous patient T cells, indicating the vaccine antigens have the potential for generating immune responses in patients previously infected MESHD or vaccinated. We further demonstrate that participants in our open-label Phase 1b study of the dual-antigen hAd5 S + N vaccine generate Th1 HGNC dominant S- and N- specific T cells after a single prime subcutaneous injection and that the magnitude of these responses were comparable to those seen for T cells from previously infected patients. We further present our in silico prediction of T-cell epitope HLA binding for both the first-wave SARS-CoV-2 A strain and the K417N, E484K, and N501Y S as well as the T201I N variants that suggests T-cell responses to the hAd5 S + N vaccine will retain efficacy against these variants. These findings that the dual-antigen hAd5 S + N vaccine elicits SARS-CoV-2-relevant T-cell responses and that such cell-mediated protection is likely to be sustained against emerging variants supports the testing of this vaccine as a universal booster that would enhance and broaden existing immune protection conferred by currently approved S-based vaccines.

    Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2

    Authors: Parakkal Deepak; Wooseob Kim; Michael A Paley; Monica Yang; Alexander B Carvidi; Alia A El-Qunni; Alem Haile; Katherine Huang; Baylee Kinnett; Mariel J Liebeskind; Zhuoming Liu; Lily E McMorrow; Diane Paez; Dana C Perantie; Rebecca E Schriefer; Shannon Sides; Mahima Thapa; Mate Gergely; Suha Abushamma; Micahel Kelbert; Lynne Mitchell; Billy Nix; Jonathan D Graf; Kimberly E Taylor; Salim Chahin; Matthew A Ciorba; Patricia A Katz; Mehrdad Matloubian; Jane A O'Halloran; Rachel M Presti; Gregory F Wu; Sean PJ Whelan; William J Buchser; Lianne S Gensler; Mary C Nakamura; Ali H Ellebedy; Alfred HJ Kim

    doi:10.1101/2021.04.05.21254656 Date: 2021-04-07 Source: medRxiv

    BackgroundIndividuals with chronic inflammatory diseases MESHD ( CID MESHD) are frequently treated with immunosuppressive medications that can increase their risk of severe COVID-19 MESHD. While novel mRNA-based SARS-CoV-2 vaccination platforms provide robust protection in immunocompetent individuals, the immunogenicity in CID MESHD patients on immunosuppression is not well established. Therefore, determining the effectiveness of SARS-CoV-2 vaccines in the setting of immunosuppression is essential to risk-stratify CID MESHD patients with impaired protection and provide clinical guidance regarding medication management. MethodsWe conducted a prospective assessment of mRNA-based vaccine immunogenicity in 133 adults with CIDs and 53 immunocompetent controls. Blood from participants over 18 years of age was collected before initial immunization and 1-2 weeks after the second immunization. Serum anti- SARS-CoV-2 spike PROTEIN (S) IgG+ binding, neutralizing antibody titers, and circulating S-specific plasmablasts were quantified to assess the magnitude and quality of the humoral response following vaccination. ResultsCompared to immunocompetent controls, a three-fold reduction in anti-S IgG titers (P=0.009) and SARS-CoV-2 neutralization (p<0.0001) were observed in CID MESHD patients. B cell depletion and glucocorticoids exerted the strongest effect with a 36- and 10-fold reduction in humoral responses, respectively (p<0.0001). Janus kinase inhibitors and antimetabolites, including methotrexate, also blunted antibody titers in multivariate regression analysis (P<0.0001, P=0.0023, respectively). Other targeted therapies, such as TNF inhibitors, IL-12/23 inhibitors, and integrin inhibitors, had only modest impacts on antibody formation and neutralization. ConclusionsCID patients treated with immunosuppressive therapies exhibit impaired SARS-CoV-2 vaccine-induced immunity, with glucocorticoids and B cell depletion therapy more severely impeding optimal responses.

    Mutations in the B.1.1.7 SARS-CoV-2 spike PROTEIN protein reduce receptor-binding affinity and induce a flexible link to the fusion peptide

    Authors: Eileen Socher; Marcus Conrad; Lukas Heger; Friedrich Paulsen; Heinrich Sicht; Friederike Zunke; Philipp Arnold

    doi:10.1101/2021.04.06.438584 Date: 2021-04-06 Source: bioRxiv

    The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. A number of single amino acid exchanges and deletions within the trimeric viral spike protein PROTEIN characterize this new SARS-CoV-2 variant. Crucial for viral entry into the host cell is the interaction of the spike protein PROTEIN with the cell surface receptor angiotensin-converting enzyme 2 ( ACE2 HGNC) as well as integration of the viral fusion peptide into the host membrane. Respective amino acid exchanges within the SARS-CoV-2 variant B.1.1.7 affect inter-monomeric contact sites within the spike protein PROTEIN (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the viral spike protein PROTEIN. However, the molecular consequences of mutations within B.1.1.7 on spike protein PROTEIN dynamics and stability, the fusion peptide, and ACE2 HGNC binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein PROTEIN trimer. In addition to reduced flexibility in the N-terminal domain of the spike protein PROTEIN, we found increased flexibility in direct spatial proximity of the fusion peptide. This increase in flexibility is due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7 found in pre- and post-cleavage state at the S2 site. Our results also imply a reduced binding affinity for B.1.1.7 with ACE2 HGNC, as the N501Y mutation restructures the RBD- ACE2 HGNC interface, significantly decreasing the linear interaction energy between the RBD and ACE2 HGNC. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD- ACE2 HGNC interface, which, in combination, might explain the higher infectivity of B.1.1.7. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7, but also other highly contagious SARS-CoV-2 variants, as many of them likewise exhibit a combination of the D614G and N501Y mutation.

    Altered O-glycosylation Level of SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN Protein by Host O-glycosyltransferase Strengthens Its Trimeric Structure

    Authors: Zhijue Xu; Xin Ku; Jiaqi Tian; Han Zhang; Jingli Hou; Can Zhang; Jingjing Shi; Yang Li; Hiroyuki Kaji; Sheng-ce Tao; Atsushi Kuno; Wei Yan; Lin-Tai Da; Yan Zhang

    doi:10.1101/2021.04.06.438614 Date: 2021-04-06 Source: bioRxiv

    The trimeric spike protein (S PROTEIN) mediates host-cell entry and membrane fusion of SARS-CoV-2. S protein PROTEIN is highly glycosylated, whereas its O-glycosylation is still poorly understood. Herein, we site-specifically examine the O-glycosylation of S protein PROTEIN through a mass spectrometric approach with HCD MESHD-triggered-ETD model. We identify 15 high-confidence O-glycosites and at least 10 distinct O-glycan structures on S protein PROTEIN. Peptide microarray assays prove that human ppGalNAc-T6 actively participates in O-glycosylation of S protein PROTEIN. Importantly, the upregulation of ppGalNAc-T6 expression can profoundly enhance the O-glycosylation level by generating new O-glycosites and increasing both O-glycan heterogeneity and intensities. Further molecular dynamics simulations reveal that the O-glycosylation on the protomer-interface regions, which are mainly modified by ppGalNAc-T6, can potentially stabilize the trimeric S protein PROTEIN structure. Our work provides deep molecular insights of how viral infection harnesses the host O-glycosyltransferases MESHD to dynamically regulate the O-glycosylation level of the viral envelope protein PROTEIN responsible for membrane fusion.

    High-Potency Polypeptide-based Interference for Coronavirus Spike Glycoproteins PROTEIN

    Authors: Jianpeng Ma; Adam Campos Acevedo; Qinghua Wang

    doi:10.1101/2021.04.05.438537 Date: 2021-04-06 Source: bioRxiv

    The world is experiencing an unprecedented coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2). SARS-CoV-2 spike PROTEIN protein-based vaccines are currently the main preventive agent to fight against the virus. However, several variants with extensive mutations in SARS-CoV-2 spike PROTEIN proteins have emerged. Some of these variants exhibited increased replication, higher transmission and virulence, and were partially resistant to antibody neutralization from natural infection or vaccination. With over 130 million confirmed cases and widespread vaccination around the globe, the emergence of new escape SARS-CoV-2 variants could be accelerated. New therapeutics insensitive to mutations are thus urgently needed. Here we have developed an inhibitor based on SARS-CoV-2 spike PROTEIN protein that potently reduced pseudovirus infectivity by limiting the level of SARS-CoV-2 spike PROTEIN proteins on virion envelope. Most importantly, the inhibitor was equally effective against other coronavirus spike proteins PROTEIN that shared as low as 35% amino-acid sequence identity, underscoring its extreme tolerance to mutations. The small-sized inhibitor would also allow simple delivery by, for instance, nasal spray. We expect the inhibitor reported here to be an invaluable aid to help end COVID-19 pandemic MESHD. Furthermore, the use of a partial native sequence or its homologues to interfere with the functions of the native protein represents a novel concept for targeting other viral proteins in combating against important viral pathogens.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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