SARS-CoV-2 proteins: Introduction

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SARS-CoV-2 is an enveloped, single-stranded positive-sense RNA virus. It was first detected in humans in late 2019 and was presumed to have emerged from a zoonotic coronavirus in an animal market in Wuhan, China [6]. SARS-CoV-2 rapidly developed to pandemic spread of a severe acute respiratory infection which was named COVID-19 to differentiate it from exisitng SARS coronavirus infections [1].

SARS-CoV-2 is a positive strand RNA virus, with similarities to the previously reported SARS coronaviruses SARS-CoV and MERS-CoV. Figure 1 is a schematic representation of the SARS-CoV-2 RNA genome. The 5′ two-thirds of the genome contains two large, overlapping open reading frames (ORF1 and ORF1b) that encode two long polyprotein precursors, pp1a and pp1ab respectively. These polyproteins are proteolytically cleaved by two integral proteases to generate 14 additional non-structural proteins (16 individual proteins in total). The remaining 3′ third of the genome encodes four structural proteins, spike (S), envelope (E), matrix (M) and nucleocapsid (N), and non-structural proteins, along with a set of accessory proteins. The viral genome hijacks the host cell replication machinery to generate all of the components that are required for self-replication, assembly and release, as well as proteins which manipulate the host's innate immune system. Of the four structural proteins, the RNA winds around the highly basic nucleocapsid (N) protein. The three other structural proteins, E, M and S, are transmembrane proteins. The E protein is a small (9-12 kDa) single transmembrane domain (1TM) protein, which enables virus assembly with the M protein, a larger (23-35 kDa) 3TM protein. Coronaviruses are named for the crown-shaped appearance of the virus due to the large (>120 kDa) S 1TM glycoprotein, which forms extended homotrimers. The SARS-CoV-2 S protein binds to human lung epithelial cells by interacting with the angiotensin-converting enzyme 2 protease on the cell surface [4-5]. This binding, under the influence of the protease TMPRSS2 facilitates viral entry into the host cells and the release of the genome [2].




Figure 2 shows the sets of proteins that are generated from the two replicase polyprotein chains that arise from overlapping ORFs at the 5' region of the SARS-CoV-2 RNA. The black arrows indicate PL-pro cleavage sites, and the small light blue arrow heads indicate Mpro cleavage sites within the C-terminal portion of the polyproteins.




Crystallisation and 3D structures of ACE2, MPRO (3CL, nsp5) and S proteins are being generated to provide insight into some of the essential protein-protein interactions and/or protein functions that are required for SARS-CoV-2 infection and replication. To date the leading candidates as novel COVID-19 therapeutic targets that have potential for pharmacological modulation are ACE2 (and its interaction with S; to reduce viral infection) and MPRO (as the key protease for replicase polyprotein processing; to inhibit virus replication).

A dedicated Coronavirus page has been created within the Guide to PHARMACOLOGY, as a portal for the rapid and frequent release of pharmacology-relevent SARS-CoV-2/COVID-19 information. A link to a review article, prepared by IUPHAR and the Guide to PHARMACOLOGY team, which offers insight into potential short- mid- and long-term anti-COVID-19 therapeutic strategies, based on sound pharmacological principles, is included on the Coronavirus page. It is forseeable that like HIV, and in light of the failure to identify monotherapeutics following the original SARS-CoV outbreak in 2003 (despite intense drug discovery activity) [3], effective treament of COVID-19 will rely on a multi-pronged approach that simultaneously targets a number of key elements such as virus replication, its route of infection and its pathological effects in the host.

Figures 1 and 2 are reproduced with permission from the Swiss Bioinformatics Institute.

References

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1. Fung TS, Liu DX. (2019) Human Coronavirus: Host-Pathogen Interaction. Annu. Rev. Microbiol., 73: 529-557. [PMID:31226023]

2. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A et al.. (2020) SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181 (2): 271-280.e8. [PMID:32142651]

3. Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. (2016) An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J. Med. Chem., 59 (14): 6595-628. [PMID:26878082]

4. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. (2020) Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, 181 (2): 281-292.e6. [PMID:32155444]

5. Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, Lu G, Qiao C, Hu Y, Yuen KY et al.. (2020) Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell, 181 (4): 894-904.e9. [PMID:32275855]

6. Zhang YZ, Holmes EC. (2020) A Genomic Perspective on the Origin and Emergence of SARS-CoV-2. Cell, 181 (2): 223-227. [PMID:32220310]

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