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SARS-CoV-2 Research Resources for Non-Structural and Accessory Proteins

Profile the Immune Response to SARS-CoV-2

Quantify SARS-CoV-2 IgG Antibody Titers with the COVID-SeroIndex ELISA

App Note: Detect ACE2 and TMPRSS2 with Simple Western

Flyer: Antibodies for COVID-19 Research

Tools to Support New Coronavirus Research

Discover Resources for SARS-CoV-2 and COVID-19

Simple Plex for COVID-19 Research

Monitor Cytokine Storm

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COVID-19 Research Blogs

SARS-CoV-2 Research Resources

SARS-CoV-2 is the etiological agent of COVID-19 and underscores the third instance of a coronavirus induced severe acute respiratory syndrome outbreak since 2002. Similar to SARS-CoV, the identified pathogen of the 2002-2003 outbreak, SARS-CoV-2 is a ~30-kb positive single-stranded RNA virus.

Genome organization of SARS-CoV-2 is similar to that of SARS-CoV, with both being organized into two main open reading frames (ORFs) and several smaller downstream ORFs. Two large ORFs, ORF1a and ORF1b, encode two polyproteins which are cleaved by viral encoded proteases resulting in several non-structural proteins (nsp). ORF1a encodes a 440-500 kDa polypeptide (pp1a) which is enzymatically processed to generate 11 nsps. The second ORF, ORF1b, encodes a larger polypeptide (pp1ab) of 740-810 kDa which is cleaved to generate 16 nsps.

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Discover small molecules for COVID-19 research from Tocris Bioscience, a Bio-Techne brand

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SARS-CoV-2 Spike Protein

The spike protein in SARS-CoV-2 (1,273 aa) is a viral surface glycoprotein with two major functional domains, the S1 (14-667 aa) and S2 (668-1255 aa) domains, which mediate cell receptor binding and membrane fusion, respectively. Viral attachment and entry into host cells is dependent on the interaction of the spike’s receptor-binding domain (RBD: 306-527 aa) with specific cellular proteins. The angiotensin converting enzyme 2 (ACE-2) and the protease TMPRSS2 have been identified as the cellular receptor and priming protease required for SARS-CoV-2 cellular entry, respectively. The protease TMPRSS2 and/or cathepsin L cleave the spike protein at the S1-S2 junction, allowing the fusion of viral envelope and cellular membranes required for viral entry. SARS-CoV-2 may also be cleaved by furin which recognizes a four amino acid sequence at the S1-S2 junction. Besides cleavage of the spike protein at the S1-S2 junction, cellular proteases cleave the S2 subunit at a recognized S2’ sequence which is critical for activation of the spike protein and consequent membrane fusion.

NYD: Not yet determined

*Solid red line: Immunogen is not known but antibody binds to RBD region (318-510 aa). Dashed red line: Exact immunogen sequence is not known.

SARS-CoV-2 Recombinant Spike Proteins

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SARS-CoV-2 Nucleocapsid Protein

The nucleocapsid phosphoprotein (419 aa) is located within the core of the SARS-CoV-2 viral particle and interacts with the viral RNA. During viral assembly, the nucleocapsid protein plays a central role in packing the viral RNA genome. This process is dependent on its ability to self-associate as previously determined for the SARS-CoV nucleocapsid protein. SARS-CoV nucleocapsid protein has been implicated in other functions such as the modulation of host cellular processes including cell cycle deregulation, inhibition of IFN production, and induction of proinflammatory factors (e.g., COX-2).

NYD: Not yet determined

Simple Western analysis of (Left) recombinant SARS-CoV-2 Nucleocapsid Protein (10474-CV) with SARS Nucleocapsid Protein Antibody [NB100-56683]. SARS Nucleocapsid protein was loaded at 20 ng/mL and detected using serial dilutions of the Rabbit Anti-SARS-CoV Nucleocapsid Protein Polyclonal Antibody (NB100-56683) followed by HRP-conjugated Anti-Goat IgG Secondary Antibody. (Right) Simple Western analysis of SARS-CoV-2 (1:50), MERS (1:100), OC43 (1:100), and 229E (1:100) lysates. A specific band was detected for SARS-CoV-2 Nucleocapsid Protein only in the SARS-CoV-2 lysate. Detection was based on the use of Rabbit Anti-SARS-CoV Nucleocapsid Protein Polyclonal Antibody [NB100-56683] followed by HRP-conjugated Anti-Goat IgG Secondary Antibody. Note: some reactivity observed with FL Std 230. SARS-CoV-2 lysate courtesy of University of Maryland. These experiments were conducted under reducing conditions and using the 12-230 kDa separation system.

A recent study developed an animal model of SARS-CoV-2 infection in rhesus macaques (now also published by Nature "Respiratory disease in rhesus macaques inoculated with SARS-CoV-2   ") and utilized the rabbit polyclonal anti SARS-CoV nucleocapsid antibody [NB100-56576] to successfully detect the presence of the SARS-CoV-2 virus in infected tissues.

Pathological changes in rhesus macaques infected with SARS-CoV-2. SARSCoV-2 nucleocapsid antigen is detected by immunohistochemistry in (g) type I pneumocytes, (j) type I pneumocytes (asterisk) and type II pneumocytes (arrow) as well as alveolar macrophages (arrowheads), (k) mediastinal lymph node, and (l) macrophages and lymphocytes in the lamina propria of the cecum. Magnification 400x. Modified from Figure 4: bioRxiv March 21, 2020 //doi.org/10.1101/2020.03.21.001628

Publication Highlight: Pathological Findings in Fatal SARS-CoV-2 Infections

To fully understand the viral cellular and tissue distribution in fatal cases of COVID-19, investigators at the Centers for Disease Control and Prevention (CDC) immunostained pulmonary tissue with SARS-CoV nucleocapsid antibody [NB100-56576]. Investigators were able to confirm the presence of SARS-CoV-2 in upper respiratory tissues and the lungs such as bronchiolar epithelium, submucosal gland epithelium, pneumocytes, and hyaline membranes in the lung. Interestingly, the virus was not detected in other organs including heart, liver, kidney, spleen, or intestinal tissue.

Immunohistochemistry: SARS Nucleocapsid Protein Antibody [NB100-56576] - Immunostaining of severe acute respiratory syndrome coronavirus 2 in pulmonary tissues from fatal coronavirus disease cases. A) P5 (Patient 5): scattered immunostaining of tracheal epithelial cells. B) P5: higher magnification shows immunostaining of ciliated cells. C) P8: immunostaining of desquamated type I pneumocyte in an alveolar lumen. D) P4: colocalization of SARS-CoV-2 viral antigen (red) with type II pneumocyte stained by surfactant (brown; arrow). E) P4: colocalization of SARS-CoV-2 viral antigen (red) with macrophages stained by CD163 (brown; arrows); virus immunostaining within type II pneumocytes is also seen (arrowheads). F) P4: extensive immunostaining of hyaline membranes in a region of exudative DAD. G) P3: scattered immunostaining within macrophage in hilar lymph node; anthracosis is also present. Emerg Infect Dis. 2020 May 21;26(9) 10.3201/eid2609.202095, PMID: 32437316

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SARS-CoV-2 Membrane and Envelope Proteins

The membrane (222 aa) and envelope (75 aa) proteins are integral proteins that function in viral assembly. SARS-CoV’s membrane protein is known to elicit the production of neutralizing antibodies in SARS patients while the envelope protein plays a role in SARS-CoV virulence and functions as an ion channel.

*NYD: Not yet determined
*N/A: Not Applicable

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Select References

Ashour, H. M., Elkhatib, W. F., Rahman, M. M., & Elshabrawy, H. A. (2020). Insights into the recent 2019 novel coronavirus (Sars-coV-2) in light of past human coronavirus outbreaks. Pathogens. https://doi.org/10.3390/pathogens9030186

Cárdenas-Conejo, Y., Liñan-Rico, A., García-Rodríguez, D. A., Centeno-Leija, S., & Serrano-Posada, H. (2020). An exclusive 42 amino acid signature in pp1ab protein provides insights into the evolutive history of the 2019 novel human-pathogenic coronavirus (SARS-CoV-2). Journal of Medical Virology. https://doi.org/10.1002/jmv.25758

Groneberg, D. A., Hilgenfeld, R., & Zabel, P. (2005). Molecular mechanisms of severe acute respiratory syndrome (SARS). Respiratory Research. https://doi.org/10.1186/1465-9921-6-8

Hoffmann, M., Kleine-Weber, H., Krüger, N., Müller, M., Drosten, C., & Pöhlmann, S. (2020). The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. BioRxiv. https://doi.org/10.1101/2020.01.31.929042

Kim, D., Lee, J.-Y., Yang, J.-S., Kim, J. W., Kim, V. N., & Chang, H. (2020). The architecture of SARS-CoV-2 transcriptome. Cell. https://doi.org/10.1016/j.cell.2020.04.011

Liu, J., Sun, Y., Qi, J., Chu, F., Wu, H., Gao, F., … Gao, G. F. (2010). The Membrane Protein of Severe Acute Respiratory Syndrome Coronavirus Acts as a Dominant Immunogen Revealed by a Clustering Region of Novel Functionally and Structurally Defined Cytotoxic T‐Lymphocyte Epitopes. The Journal of Infectious Diseases. https://doi.org/10.1086/656315

Millet, J. K., & Whittaker, G. R. (2015). Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Research. https://doi.org/10.1016/j.virusres.2014.11.021

Munster, V., Feldmann, F., Williamson, B., Doremalen, N. van, Lizzette Perez-Perez, Schultz, J., … Wit, E. de. (2020). Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2. BioRxiv. https://doi.org/10.1101/2020.03.21.001628

Ortega, J. T., Serrano, M. L., Pujol, F. H., & Rangel, H. R. (2020). Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: An in silico analysis. EXCLI J. https://doi.org/10.17179/excli2020-1167

Pervushin, K., Tan, E., Parthasarathy, K., Lin, X., Jiang, F. L., Yu, D., … Torres, J. (2009). Structure and inhibition of the SARS coronavirus envelope protein ion channel. PLoS Pathogens. https://doi.org/10.1371/journal.ppat.1000511

Prajapat, M., Sarma, P., Shekhar, N., Avti, P., Sinha, S., Kaur, H., … Medhi, B. (2020). Drug targets for corona virus: A systematic review. Indian Journal of Pharmacology. https://doi.org/10.4103/ijp.IJP_115_20

Schoeman, D., & Fielding, B. C. (2019). Coronavirus envelope protein: Current knowledge. Virology Journal. https://doi.org/10.1186/s12985-019-1182-0

Surjit, M., & Lal, S. K. (2008). The SARS-CoV nucleocapsid protein: A protein with multifarious activities. Infection, Genetics and Evolution. https://doi.org/10.1016/j.meegid.2007.07.004

Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T., & Veesler, D. (2020). Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. https://doi.org/10.1016/j.cell.2020.02.058

Wu, C., Liu, Y., Yang, Y., Zhang, P., Zhong, W., Wang, Y., … Li, H. (2020). Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharmaceutica Sinica B. https://doi.org/10.1016/j.apsb.2020.02.008