WikiJournal Preprints/The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19

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The devastating effects of the recent global pandemic (termed COVID-19 for “coronavirus disease 2019”) caused by the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) are paramount with new cases and deaths growing at an exponential rate. In order to provide a better understanding of SARS CoV-2, this article will review the proteins found in the SARS CoV-2 that caused this global pandemic.

Introduction edit

Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) is the virus that caused the global pandemic that was first reported[1] on December 31, 2019.[2] Taxonomically, SARS CoV-2 belongs to the realm Riboviria, order Nidovirales, suborder Cornidovirineae, family Coronaviridae, subfamily Orthocoronavirinae, genus Betacoronavirus (lineage B),[3] subgenus Sarbecovirus, and the species Severe acute respiratory syndrome-related coronavirus.

The genome of SARS CoV-2 (NCBI Reference Sequence: NC_045512.2)[4] is similar to the genome of the coronavirus that caused the SARS epidemic in 2003 (SARS CoV, NCBI Reference sequence: NC_004718.3).[5][6] Much of the understanding of the proteins found in SARS CoV-2 are based on the numerous research studies reported on SARS CoV and other related viruses (e.g. MERS CoV).[7][8] However, among the recent coronavirus outbreaks in the new millennium (SARS CoV: 2002-2003, MERS CoV: 2012, SARS CoV-2: 2020), SARS CoV-2 mysteriously had the most devastating global impact. Understanding the proteins present in these viruses enable a more rational approach to designing more effective antiviral drugs.[9][10] The majority of proteins of SARS CoV have been characterized in detail. The proteins of SARS CoV consist of two large polyproteins: ORF1a and ORF1ab (that proteolytically cleave to form 16 nonstructural proteins), four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N), and eight accessory proteins: ORF3a, ORF3b (NP_828853.1, not present in SARS CoV-2), ORF6, ORF7a, ORF7b, ORF8a, ORF8b, and ORF9b (NP_828859.1, not present in SARS CoV-2). Although accessory proteins have been viewed as dispensable for viral replication in vitro, some have been shown to play an important role in virus-host interactions in vivo.[11] Similar to SARS CoV, SARS CoV-2 lacks the hemagglutinin esterase gene, which is found in human coronavirus (hCoV) HKU1, a lineage A betacoronavirus.[3] The spike protein, envelope protein, membrane protein, nucleocapsid protein, 3CL protease, papain like protease, RNA polymerase,[10] and helicase protein have been suggested to be viable antiviral drug targets.[12] SARS CoV-2 is an RNA virus and its RNA genome is 30 kb in length. SARS CoV-2 is thought to have originated from its closest relative, BatCov RaTG13 (GenBank: MN996532),[13] which was isolated from horseshoe bats.[14]

Discussion: Proteins of SARS CoV-2 edit

SARS CoV-2 (NC_045512.2) has a total of 11 genes with 11 open reading frames (ORFs) (Table 1): ORF1ab, ORF2 (Spike protein), ORF3a, ORF4 (Envelope protein), ORF5 (Membrane protein), ORF6, ORF7a, ORF7b, ORF8, ORF9 (Nucleocapsid protein), and ORF10.

Table 1. The genes expressed by SARS CoV-2 (NC_045512.2).
Number Length (a.a.) Gene GeneID Location Protein [LOCUS]
1a 7,096 ORF1ab 43740578 266-21,555 ORF1ab polyprotein [BCB15089.1/BCB97900.1]
1b 4,405 ORF1a 43740578 266-13,483 ORF1a polyprotein [YP_009725295.1]
2 1,273 ORF2 (S) 43740568 21,563-25,384 Spike protein (S protein) [BCA87361.1]
3 275 ORF3a 43740569 25,393-26,220 ORF3a protein [BCA87362.1]
4 75 ORF4 (E) 43740570 26,245-26,472 Envelope protein (E protein) [BCA87363.1]
5 222 ORF5 (M) 43740571 26,523-27,191 Membrane protein (M protein) [BCA87364.1]
6 61 ORF6 43740572 27,202-27,387 ORF6 protein [BCA87365.1]
7 121 ORF7a 43740573 27,394-27,759 ORF7a protein [BCA87366.1]
8 43 ORF7b 43740574 27,756-27,887 ORF7b protein [BCB15096.1]
9 121 ORF8 43740577 27,894-28,259 ORF8 protein [BCA87367.1]
10 419 ORF9 (N) 43740575 28,274-29,533 Nucleocapsid phosphoprotein (N protein) [BCA87368.1]
11 38 ORF10 43740576 29,558-29,674 ORF10 protein [BCA87369.1]

1. Polyprotein expressed by ORF1ab edit

The first gene (ORF1ab) expresses a polyprotein. The ORF1ab polyprotein is comprised of 16 nonstructural proteins (NSPs) (Table 2).

Table 2. The nonstructural proteins (NSPs) found in the polyprotein of SARS CoV-2.
# Name Accession Length (a.a) Proposed function Notes possible antiviral target
(i) NSP1 YP_009725297.1 180 amino acids induce host mRNA cleavage leader protein
(ii) NSP2 YP_009725298.1 638 amino acids Binds to PHBs 1, 2
(iii) NSP3 YP_009725299.1 1,945 amino acids Release NSPs 1, 2, 3 Papain like proteinase yes
(iv) NSP4 YP_009725300.1 500 amino acids Membrane rearrangement
(v) NSP5 YP_009725301.1 306 amino acids Cleaves at 11 sites of NSP polyprotein 3C-like proteinase yes
(vi) NSP6 YP_009725302.1 290 amino acids Generates autophagosomes
(vii) NSP7 YP_009725303.1 83 amino acids dimerizes with NSP8
(viii) NSP8 YP_009725304.1 198 amino acids stimulates NSP12
(ix) NSP9 YP_009725305.1 113 amino acids binds to helicase(?)
(x) NSP10 YP_009725306.1 139 amino acids Stimulates NSP16(?)
(xi) NSP11 YP_009725312.1 13 amino acids unknown
(xii) NSP12 YP_009725307.1 932 amino acids Copies viral RNA RNA polymerase yes
(xiii) NSP13 YP_009725308.1 601 amino acids unwinds duplex RNA Helicase
(xiv) NSP14 YP_009725309.1 527 amino acids 5’-cap RNA methylation (guanine) 3’ to 5’ exonuclease, guanine N7-methyltransferase
(xv) NSP15 YP_009725310.1 346 amino acids degrade RNA to evade host defense endoRNAse/endoribonuclease yes
(xvi) NSP16 YP_009725311.1 298 amino acids 5’-cap RNA methylation (adenine) 2’-O-ribose-methyltransferase - potential antiviral drug target

(i) NSP1 (Leader protein) edit

Nonstructural protein 1 (NSP1) is the first protein of the polyprotein of SARS CoV-2 (Figure 1 – sequence alignment of NSP1 for SARS CoV with SARS CoV-2). This protein is also known as the leader protein. This protein is also found in SARS coronavirus and is known to be a potent inhibitor of host gene expression. NSP1 binds to the 40S ribosome of the host cell to inactivate translation and promotes host mRNA degradation selectively, while the viral SARS CoV mRNA remain intact.[15] Figure 1 shows the amino acid sequence alignment for the NSP1 proteins of SARS CoV (from genome: NCBI Reference Sequence: NC_004718.3) and SARS CoV-2.


 Alignment of the primary amino acid sequence of NSP1 of SARS CoV (top, NP_828860.2) and SARS CoV-2 (YP_009725297.1). Sequence identity: 84.4%. Sequence similarity: 93.9%.

Determined using LALIGN software (and for subsequent alignments, Figures 2-26, see Supporting Information for output data).[16]

(ii) NSP2 edit

Nonstructural protein 2 (NSP2) is the second protein of the polyprotein of SARS CoV-2 (Figure 2). This protein is conserved in SARS CoV, the related beta coronavirus to SARS CoV-2. In SARS CoV, NSP2 was found to bind to two host proteins: prohibitin 1 and prohibitin 2 (PHB1 and PHB2).[17] PHB1 and PHB2 proteins are known to play roles in cell cycle progression, cell migration, cellular differentiation, apoptosis, and mitochondrial biogenesis. The binding of NSP2 to PHB1 and PHB2 proteins suggest that NSP2 plays a role in disrupting the host cell environment. The amino acid sequence alignment for NSP2 of SARS CoV and SARS CoV-2 is shown in Figure 2.


 The primary amino acid sequence alignment of NSP2 for SARS CoV (NP_828861.2) and SARS CoV-2 (YP_009725298.1). These proteins have 68.3% sequence identity (90.0% similar).

(iii) NSP3 (Papain like proteinase)  edit

NSP3 is the papain-like proteinase protein (Figure 3). This protein is nearly 200 kDa in size and is the largest protein (not including the polyproteins ORF1a and ORF1ab) encoded by the coronaviruses. With such a long sequence, it possesses several conserved domains: ssRNA binding, ADPr binding, G-quadruplex binding, ssRNA binding, protease (papain-like protease), and NSP4 binding), and transmembrane domain. Among the 16 nonstructural proteins, NSP3, NSP4, and NSP6 have transmembrane domains.[18] The papain like protease 1 (PL1 protease) of alpha coronavirus (alpha CoV) Transmissible Gastroenteritis Virus (TGEV), which is part of NSP3, was shown to cleave the site between NSP2 and NSP3. Furthermore, this papain like protease domain is responsible for the release of NSP1, NSP2, and NSP3 from the N-terminal region of polyproteins 1a and 1ab from coronaviruses.[19] Considering this important protease activity to release essential proteins for viral activity, the inhibition of NSP3 protease activity is an important target for antiviral activity.[20] Tanshinones, a class of natural products have been found to inhibit NSP3 protease activity. The amino acid sequence alignment for the NSP3 protein of SARS CoV and SARS CoV-2 is shown in Figure 3.


 The primary amino acid sequence alignment of NSP3 for SARS-CoV (NP_828862.2) and SARS CoV-2 (YP_009725299.1). Sequence identity: 76%, sequence similarity: 91.8%.

(iv) NSP4 (contains transmembrane domain 2) edit

NSP4 interacts with NSP3 and possibly host proteins to confer a role related to membrane rearrangement in SARS CoV. Moreover, the interaction between NSP4 and NSP3 is essential for viral replication.[18] The sequence alignment for NSP4 proteins for SARS CoV and SARS CoV-2 is shown in Figure 4.


 The primary amino acid sequence alignment of NSP4 for SARS CoV (NP_904322.1) and SARS CoV-2 (YP_009725300.1). Sequence identity: 80.0%, sequence similarity: 95.0%.

(v) NSP5 (3C-like proteinase) edit

The NSP5 protein based on the Middle East Respiratory Syndrome (MERS) coronavirus has been characterized. NSP5 cleaves at 11 distinct sites to yield mature and intermediate nonstructural proteins (NSPs).[21] The amino acid sequence alignment for NSP5 of SARS CoV and SARS CoV-2 is shown in Figure 5.


 The primary amino acid sequence alignment of NSP5 for SARS CoV (NP_828863.1) and SARS CoV-2 (YP_009725301.1). Sequence identity: 96.1%, sequence similarity: 99.7%.

(vi) NSP6 (putative transmembrane domain) edit

The NSP6 protein of the avian coronavirus (infectious bronchitis virus, IBV) was shown to generate autophagosomes from the endoplasmic reticulum (ER) (Figure 6B shows sequence alignment with SARS CoV-2 NSP6). Autophagosomes facilitate assembly of replicase proteins. Furthermore, NSP6 limited autophagosome/lysosome expansion, which in turn prevents autophagosomes from delivering viral components for degradation in lysosomes.[22] With SARS CoV, NSP6 was shown to induce membrane vesicles.[23] The amino acid sequence alignment for NSP6 of SARS CoV and SARS CoV-2 is shown in Figure 6.


 Amino acid sequence alignment between the NSP6 proteins of SARS CoV (top: NP_828864.1) and SARS CoV-2 (bottom: YP_009725302.1). Sequence identity: 88.2%, sequence similarity: 98.3%.

(vii) NSP7 edit

NSP7 is required to form a complex with NSP8 (next section) and NSP12 to yield the RNA polymerase activity of NSP8.[24] The primary amino acid sequence alignment for the NSP8 proteins for SARS CoV and SARS CoV-2 is shown in Figure 7. Only one amino acid residue is different (arginine vs. lysine) but the charge is conserved at this location.


 The primary amino acid sequence alignment of NSP7 SARS CoV (NP_828865.1) and SARS CoV-2 (YP_009725303.1). Sequence identity: 98.8%, sequence similarity: 100%.

(viii) NSP8 edit

NSP8 is a peptide cofactor that makes a heterodimer with NSP7 (the other peptide cofactor), and this NSP7-NSP8 heterodimer complexes with NSP12. In addition to the NSP7-NSP8 heterodimer, an NSP8 monomer unit also complexes with NSP12, which ultimately forms the RNA polymerase complex. The cryo-EM structure of this complex has been solved.[25] The amino acid sequence alignment for NSP8 of SARS CoV and SARS CoV-2 is shown in Figure 8.


 The primary amino acid sequence alignment of NSP8 for SARS CoV (NP_828866.1) and SARS CoV-2 (YP_009725304.1). Sequence identity: 97.5%, sequence similarity: 100.0%.

(ix) NSP9 edit

NSP9 from the porcine reproductive and respiratory syndrome virus (PRRSV) has been found to interact with the DEAD-box RNA helicase 5 (DDX5) cellular protein.[26] This interaction between NSP9 and DDX5 has been shown to be important for viral replication – when the DDX5 gene was silenced in MARC-145 cells, the virus titers were lower by 10-fold. Figure 9 shows the amino acid sequence alignment between the two NSP9 proteins from SARS CoV and SARS CoV-2.


 The primary amino acid sequence alignment of NSP9 for SARS CoV (NP_828868.1) and SARS CoV-2 (YP_009725305.1). Sequence identity: 97.3%, sequence similarity: 99.1%.

(x) NSP10 edit

NSP10 has been shown to interact with NSP14 in SARS coronavirus, and this interaction stimulates activity of NSP14. NSP 14 is known to function as an S-adenosylmethionine (SAM)-dependent (guanine-N7) methyl transferase (N7-MTase).[27] Furthermore, NSP10 has also been shown to stimulate the activity of NSP16, which is a 2’-O-methyltransferase.[28] Figure 10 shows the amino acid sequence alignment between the two NSP10 proteins from SARS CoV and SARS CoV-2.


 The primary amino acid sequence alignment of NSP10 for SARS CoV (NP_828868.1) and SARS CoV-2 (YP_009725306.1). Sequence identity:97.1 %, sequence similarity: 99.3%.

(xi) NSP11 edit

The function of NSP11 seems to be unknown. NSP11 is made of thirteen amino acids and the first nine amino acids (sadaqsfln) are identical to the first nine in NSP12. Figure 11 shows the amino acid sequence alignment between the two NSP12 proteins from SARS CoV and SARS CoV-2.


 The primary amino acid sequence alignment of NSP11 for SARS CoV (NP_904321.1) and SARS CoV-2 (YP_009725312.1). Sequence identity: 84.6%, sequence similarity: 100.0%.

(xii) NSP12 (RNA dependent RNA polymerase) edit

NSP12 is the RNA-dependent RNA polymerase that copies viral RNA. As mentioned, NSP12 makes a complex with an NSP7-NSP8 heterodimer and an NSP8 monomer to confer processivity of NSP12. NSP12 exhibits poor processivity in RNA synthesis – that is the presence of NSP7 and NSP8 lowers the dissociation rate of NSP12 from RNA.[29] The amino acid sequence alignment between the two NSP12 proteins from SARS CoV and SARS CoV-2 is shown in Figure 12.


 The primary amino acid sequence alignment of NSP12 for SARS CoV (NP_828869.1) and SARS CoV-2 (YP_009725307.1). Sequence identity: 96.4%, sequence similarity: 99.4%.

(xiii) NSP13 (helicase) edit

SARS CoV was used to characterize the helicase enzyme, NSP13, which unwinds duplex RNA.[30] The crystal structure of NSP13 of SARS CoV has been reported.[31] Furthermore, it has been shown that binding of NSP12 with NSP13 can enhance the helicase activity of NSP13. In addition to its helicase activity, NSP13 of SARS CoV is also known to possess 5’-triphosphatase activity, which is responsible for introducing the 5’-terminal cap of the viral mRNA.[32] Both eukaryotic and most viral mRNA have a 5’-terminal cap structure: m7G(5)ppp(5)N-. This 5’-terminal cap is the site of recognition for translation and plays a role in splicing, nuclear export, translation, and stability of mRNA. This process of incorporating the 5’-terminal cap will be discussed in the next section: (xiv) NSP14. The sequence alignment for NSP13 of SARS CoV and SARS CoV-2 is shown in Figure 13. Interestingly, only one amino acid residue is different out of the 601 amino acids in these two proteins (isoleucine vs. valine).


 The primary amino acid sequence alignment of NSP13 for SARS CoV (NP_828870.1) and SARS CoV-2 (YP_009725308.1). Sequence identity: 99.8%, sequence similarity: 100.0%.

(xiv) NSP14 (3’ to 5’ endonuclease, N7-Methyltransferase) edit

NSP14 from coronavirus is known to have 3’-5’ exoribonuclease activity and N7-methyltransferase activity.[33] The guanine-N7-methyltransferase activity is part of the process for introducing the 5’-cap of the virus, which involves multiple steps: (1) the gamma-phosphate of the 5’end of nascent mRNA is removed by the RNA triphosphatase (NSP13),[32] (2) a GMP moiety derived from a covalent enzyme-GMP intermediate is transferred to the resulting mRNA with a diphosphate end, (3) the GpppA cap is methylated with S-adenosyl-methionine, which is catalyzed by the guanine-N7-methyltransferase (NSP14) to yield the cap-0 structure,[34] and (4) 2’-O-methylation by NSP16 of adenine gives the cap-1 structure.[35] It is currently unknown which enzyme incorporates the GMP group involved in the second step, and it is possible that the virus uses the host guanylyltransferase enzyme.[36] Figure 14 shows the amino acid sequence alignment between the NSP14 proteins of SARS CoV and SARS CoV-2.


 The primary amino acid sequence alignment of NSP14 for SARS CoV (NP_828871.1) and SARS CoV-2 (YP_009725309.1). Sequence identity: 95.1%, sequence similarity: 99.1%.

(xv) NSP15 (endoRNAse) edit

NSP15 of SARS coronavirus has been biochemically characterized as an endoribonuclease that cleaves RNA at uridylates at the 3’-position to form a 2’-3’ cyclic phosphodiester product.[37] The NSP15 protein specifically targets and degrades the viral polyuridine sequences to prevent the host immune sensing system from detecting the virus.[38] The crystal structure of NSP15 has been reported for SARS CoV[39] and SARS CoV-2.[40] NSP15 uses manganese as a cofactor to promote endoribonuclease activity.[41] It has been suggested that NSP15 degrades viral dsRNA to prevent host recognition.[42] The amino acid sequence alignment of NSP15 from SARS CoV and SARS CoV-2 is shown in Figure 15.


 The primary amino acid sequence alignment of NSP15 for SARS CoV (NP_828872.1) and SARS CoV-2 (YP_009725310.1). Sequence identity: 88.7%, sequence similarity: 97.7%

(xvi) NSP16 (2’-O-ribose-methyltransferase) edit

NSP16 for coronavirus has been biochemically[43] (feline coronavirus, FCoV) and structurally[44] (complex of NSP10-NSP16 for SARS CoV) characterized. The viral RNA has a 5’-cap, which protects it from mRNA degradation by 5’-exoribonucleases, promotes mRNA translation, and prevents the viral RNA from being recognized by innate immunity mechanisms.[44] The RNA cap is an N7-methylated guanine nucleotide connected through a 5’-5’ triphosphate bridge to the first transcribed nucleotide (adenine). NSP16 methylates the 2’-hydroxy group of adenine using S-adenosylmethionine as the methyl source. Figure 16 shows the amino acid sequence alignment between the two NSP16 proteins from SARS CoV and SARS CoV-2.


 The primary amino acid sequence alignment of NSP16 for SARS CoV (NP_828873.2) and SARS CoV-2 (YP_009725311.1). Sequence identity: 93.3%, sequence similarity: 99.0%.

2. Spike Protein (surface glycoprotein) edit

The spike protein (Figure 17 – sequence alignment between SARS CoV and SARS CoV-2) is a glycoprotein, which mediates attachment of the virus to the host cell. The electron microscopy structures of the spike (S) protein for both SARS CoV-2 (PDB: 6VXX​)[45] and SARS CoV (PDB: 5XLR​)[46] have been determined. This protein recognizes the human angiotensin-converting enzyme 2 (ACE2) protein on the host cell surface.[45][47][48] SARS CoV spike mouse polyclonal antibodies potently inhibited SARS CoV-2 spike protein mediated entry into cells.[45] Interestingly, a furin cleavage site (highlighted in Figure 17: QTQTNSPRRARSVASQSIIA) was located in the S protein of SARS CoV-2, which was lacking in the S protein of SARS CoV. This difference in site could possibly explain the difference in pathogenicity of these two viruses.[45] This particular furin cleavage site ([R/K]-[2X]n-[R/K]↓) has been identified in the spike proteins of other coronaviruses: HCoV-OC43, MERS-CoV, and HKU1[49] but is clearly not present in SARS CoV (Figure 17 sequence alignment).


 The primary amino acid sequence alignment of the spike proteins from SARS CoV (NP_828851.1) and SARS CoV-2 (BCA87361.1). Sequence identity: 76.0%, sequence similarity: 91.5%.

3. ORF3a protein edit

The ORF3a protein from SARS CoV is an ion channel protein related to NLRP3 inflammasome activation. ORF3a interacts with TRAF3, which in turn activates ASC ubiquitination, and as a result, leads to activation of caspase 1 and IL-1b maturation.[50] The amino acid sequence alignment between the two ORF3a proteins from SARS CoV and SARS CoV-2 is shown in Figure 18.


 The primary amino acid sequence alignment of the ORF3a proteins from SARS CoV (NP_828852.2) and SARS CoV-2 (BCA87362.1). Sequence identity: 72.4%, sequence similarity: 90.2%.

4. Envelope protein edit

The envelope protein is a small integral membrane protein in coronaviruses, which can oligomerize and create an ion channel.[51] The four structural proteins of coronaviruses are: S protein, M protein, E protein, and N protein.[52] The E protein has been shown to play multiple roles in the viral replication cycle: (1) viral assembly,[53] (2) virion release,[54] and (3) viral pathogenesis.[55] Interestingly, in the sequence alignment of the E proteins from SARS CoV and SARS CoV-2 (Figure 19), there is a glutamate residue (E69) with a negative charge in SARS CoV that corresponds to a positively charged arginine in SARS CoV-2 (R69).


 The primary amino acid sequence alignment of the E proteins (ORF4) from SARS CoV (NP_828854.1) and SARS CoV-2 (BCA87363.1). Sequence identity: 94.7%, sequence similarity: 97.4%.

5. Membrane protein edit

The SARS coronavirus membrane (M) protein is an integral membrane protein that plays an important role in viral assembly.[56] In addition, the SARS coronavirus M protein has been shown to induce apoptosis.[57] The M protein interacts with the nucleocapsid (N) protein to encapsidate the RNA genome.[58] Figure 20 shows the amino acid sequence alignment of the two ORF5 proteins from SARS CoV and SARS CoV-2.


 The primary amino acid sequence alignment of the M proteins (ORF5) from SARS CoV (NP_828855.1) and SARS CoV-2 (BCA87364.1). Sequence identity: 90.5%, sequence similarity: 98.2%.

6. ORF6 protein edit

The ORF6 protein from SARS coronavirus is an accessory protein that plays an important role in viral pathogenesis.[59][60] Using a yeast two-hybrid system, ORF6 was shown to interact with NSP8, the nonstructural protein related to promoting RNA polymerase activity.[61] Figure 21 shows the amino acid sequence alignment of the two ORF6 proteins from SARS CoV and SARS CoV-2.


 The primary amino acid sequence alignment of the ORF6 proteins from SARS CoV (NP_828856.1) and SARS CoV-2 (BCA87365.1). Sequence identity: 68.9%, sequence similarity: 93.4%.

7. ORF7a protein edit

ORF7a from SARS coronavirus is an accessory protein that is a type I transmembrane protein and its crystal structure has been determined.[61] Figure 22 shows the amino acid sequence alignment between the two ORF7a proteins of SARS CoV and SARS CoV-2.


 The primary amino acid sequence alignment of the ORF7a proteins from SARS CoV (NP_828857.1) and SARS CoV-2 (BCA87366.1). Sequence identity: 85.2%, sequence similarity: 95.9%.

8. ORF7b protein edit

The ORF7b accessory protein from SARS coronavirus is localized in the Golgi compartment.[62] Figure 23 shows the sequence alignment between the two ORF7b proteins of SARS CoV and SARS CoV-2.


 The primary amino acid sequence alignment of the ORF7b proteins from SARS CoV (NP_849175.1) and SARS CoV-2 (BCA15096.1). Sequence identity: 85.4%, sequence similarity: 97.2%.

9. ORF8 protein edit

SARS CoV-2 has a single ORF8 protein while SARS CoV has two ORF8 proteins: ORF8a and ORF8b.[63] In SARS CoV, the ORF8b protein binds to the IRF association domain (IAD) region of interferon regulatory factor 3 (IRF3), which in turn inactivates interferon signaling.[64] Interestingly, L84S and S62L missense mutations have been reported in various SARS CoV-2 sequences.[5] Figure 24 shows the alignment between the ORF8 protein of SARS CoV-2 with the ORF8a and ORF8b proteins of SARS CoV.


 Sequence alignment of ORF8a (NP_849176.1) and ORF8b (NP_849177.1) proteins from SARS CoV (top and middle) with the ORF8 protein (QJA17759.1) from SARS CoV-2 (bottom). Sequence identity and sequence similarity between ORF8a (SARS CoV) and ORF8 (SARS CoV-2): 31.7% and 70.7% in 41 amino acid overlap. Sequence identity and sequence similarity between ORF8b (SARS CoV) and ORF8 (SARS CoV-2): 40.5% and 66.7% in 42 amino acid overlap.

10. Nucleocapsid protein edit

The nucleocapsid (N) protein of coronaviruses is a structural protein that binds directly to viral RNA and providing stability.[65] Furthermore, the N protein of SARS CoV-2 (Figure 24) has been found to antagonize antiviral RNAi.[66] In another study, the nucleocapsid protein of SARS CoV was found to inhibit the activity of cyclin-cyclin-dependent kinase (cyclin-CDK) complex. Inactivation of the cyclin-CDK complex results in hypophosphorylation of the retinoblastoma protein and in turn inhibits S phase (genome replication) progression in the cell cycle.[67] Figure 25 shows the amino acid sequence alignment between the two N proteins of SARS CoV and SARS CoV-2.


 The primary amino acid sequence of the N protein from SARS CoV (ORF9a, NP_828858.1) and SARS CoV-2 (ORF9, BCA87368.1). Sequence identity: 90.5%, sequence similarity: 97.2%.

11. ORF10 protein edit

ORF10 protein from SARS CoV-2 is comprised of 38-amino acids and its function is unknown. Interestingly, SARS CoV possesses an ORF9b protein (NP_828859.1), which is not present in SARS CoV-2. Figure 26 shows the sequence alignment between ORF10 of SARS CoV-2 with ORF9b of SARS CoV. SARS CoV-2 does not have an ORF10 protein. A summary of the sequence identities and similarities of the discussed proteins from SARS CoV and SARS CoV-2 is shown in Table 4.


 The primary amino acid sequence alignment of the ORF9b protein from SARS CoV and the ORF10 protein from SARS CoV-2 (Accession number: BCA87369.1). Sequence identity: 28.6%, sequence similarity: 52.4%.

Table 4. Sequence identity and similarities between SARS CoV-2 proteins and SARS CoV proteins determined through LALIGN[16] (see Supporting Information). “*”: (SARS CoV-2 protein vs SARS CoV protein). Other reports have also reported amino acid sequence identities using different algorithms.[3][68]
Entry Protein Amino Acid Overlap Sequence Identity Sequence Similarity
1 NSP1 180 84.4% 93.4%
2 NSP2 638 68.3% 90.0%
3 NSP3 1,952 76.0% 91.8%
4 NSP4 500 80.0% 95.0%
5 NSP5 306 96.1% 99.7%
6 NSP6 287 88.2% 98.3%
7 NSP7 83 98.8% 100.0%
8 NSP8 198 97.5% 100.0%
9 NSP9 113 97.3% 99.1%
10 NSP10 139 97.1% 99.3%
11 NSP11 13 84.6% 100.0%
12 NSP12 932 96.4% 99.4%
13 NSP13 601 99.8% 100.0%
14 NSP14 527 95.1% 99.1%
15 NSP15 346 88.7% 97.7%
16 NSP16 298 93.3% 99.0%
17 S protein 1,277 76.0% 91.5%
18 ORF3a 1,381 72.4% 90.2%
19 E protein 76 94.7% 97.4%
20 M protein 222 90.5% 98.2%
21 ORF6 61 68.9% 93.4%
22 ORF7a 122 85.2% 95.9%
23 ORF7b 41 85.4% 92.7%
24a (ORF8 vs 8a)* 41 31.7% 70.7%
24b (ORF8 vs 8b)* 42 40.5% 66.7%
25 N Protein 422 90.5% 97.2%
26 (ORF10 vs 9b)* 21 28.6% 52.4%

Available Structures of SARS CoV-2 Proteins edit

A major thrust of research of SARS CoV-2 proteins is the elucidation of the 3-dimensional structures of the proteins determined through X-ray crystallography or electron microscopy. Table 5 summarizes efforts to elucidate the structures of each of these proteins. The images of structures were produced using Chimera software.[69]

Table 5. Summary of the available 3-dimensional structures of SARS CoV-2 proteins.
Entry Description of Structure PDB ID Structure Ref.
1 S protein (electron microscopy) PDB: 6VXX
2 S protein (cryo-EM) with ACE2 PDB: 6M0J
4 NSP3 (papain like protease) PDB: 6W9C
5 NSP5 (3CL-protease) PDB: 6M2N
6 NSP5 (3CL-protease) PDB: 6Y2G
8 NSP9 PDB: 6W4B
9 NSP7-NSP8-NSP12 (cryo-EM) PDB: 7BV2
10 NSP7-NSP8-NSP12 (apo) (cryo-EM) PDB: 7BV1
11 NSP10-NSP16 (7-Me-GpppA) PDB: 6WQ3
12 NSP10-NSP16 (sinefungin) PDB: 6WKQ
13 NSP15 PDB: 6VWW
14 ORF7a PDB: 6W37
15 ORF9 (N Protein) PDB: 6WJI

Overlapping Genes: ORF9b and Two Proteins with Variation Among SARS CoV-2 Sequences: ORF3b and ORF9c edit

Overlapping genes in coronavirus have been previously observed.[81] For example, in SARS CoV, the start and end positions in the nucleotide sequence of the N-protein are 28,120 and 29,388 respectively while the ORF9b gene of SARS CoV starts and ends at positions: 28,130 and 28,426 (within the gene sequence of the N-protein).[82] Similarly, there is a putative ORF9b protein in SARS CoV-2 located within the gene encoding the N-protein, which does not yet have an accession number.[4]

In the gene alignment of 2,784 SARS CoV-2 sequences, two variations were recognized in the SARS CoV-2 genome.[68] It was recognized that a premature stop codon at position 14 of ORF3b in SARS CoV-2 in 17.6% of isolates (position E14). Furthermore, there were two mutations that gave rise to premature stop codons in ORF9c (at position Q41 in 0.7% of sequences and at position Q44 in 1.4% of the sequences). The observations of these stop codons suggested that these genes for ORF3b and ORF9c may not be bonafide gene sequences in SARS CoV-2. With the putative SARS CoV-2 ORF3b protein, only 12 out of 57 overlapping amino acid residues were identical (21% sequence identity) to the ORF3b protein of SARS CoV.[3] In the above sections, ORF3b and ORF9c for SARS CoV-2 were not included in the above analysis. Another protein lacking an accession number is ORF14.[83]

Exploration of Treatment Options for COVID-19 edit

An intense effort has been put forth to discover potential treatment options for COVID-19, the disease caused by SARS CoV-2.[84][85][86] For instance, the FDA approved drug, ivermectin, is known to inhibit nuclear transport, and has been shown to inhibit the replication of SARS CoV-2.[87] Other drugs have been repurposed and tested against COVID-19.[88][89] Remdesivir is a potential antiviral drug originally developed to treat ebola[90] and has been used to treat COVID-19[91] by inhibiting viral RNA polymerase activity. Hydroxychloroquine[92] and chloroquine[93] have been used to potentially treat COVID-19. However, the use of these drugs has been known to result in cardiotoxicity.[94][95] In fact, in a recent observational study, it was determined that hydroxychloroquine administration was not associated with a greatly lowered risk of death from COVID-19.[96]

Traditional Chinese Medicine (TCM) has also been employed in China to treat COVID-19.[97] However, due to potential toxic components present in TCM remedies,[98][99] the use of this strategy should be handled with caution.[100] Ironically, it has been suggested that TCM could have potentially been the cause of COVID-19.[101]

In addition to small molecules, vaccines are also currently being developed against SARS CoV-2,[102] and convalescent plasma transfusions have been used to treat COVID-19.[103] Nevertheless, more research is needed to develop effective treatments against SARS CoV-2 especially in the context of future outbreaks.[104][105]

Conclusion edit

Although there is some variation in sequence in the proteins, many of the proteins found in SARS CoV-2 (NC_045512.2) are also found in SARS CoV (AY515512.1 or NC_004718.3) with 77.1% of the protein sequences shared in their proteomes.[106] Thus, previous research on related coronavirus proteins enable a better understanding of how we can approach to understand the current coronavirus (SARS CoV-2) that caused the current global pandemic (COVID-19). The general structures of most of the proteins from SARS CoV-2 can be visualized from homology models.[107] Advances in the knowledge of the structures and functions of the proteins in SARS CoV-2 will enable researchers to design better antiviral drugs that target this virus.

Additional information edit

Acknowledgements edit

Francis K. Yoshimoto, PhD holds a Voelcker Fund Young Investigator Award from the MAX AND MINNIE TOMERLIN VOELCKER FUND.

Competing interests edit

The author has no competing interest.

Ethics statement edit

Not applicable.

References edit

  1. Li, Xingguang; Zai, Junjie; Wang, Xiaomei; Li, Yi (2020-02-14). "Potential of large “first generation” human‐to‐human transmission of 2019‐nCoV". Journal of Medical Virology 92 (4): 448–454. doi:10.1002/jmv.25693. ISSN 0146-6615. 
  2. Gralinski, Lisa E.; Menachery, Vineet D. (2020-01-24). "Return of the Coronavirus: 2019-nCoV". Viruses 12 (2): 135. doi:10.3390/v12020135. ISSN 1999-4915. 
  3. 3.0 3.1 3.2 3.3 Chan, Jasper Fuk-Woo; Kok, Kin-Hang; Zhu, Zheng; Chu, Hin; To, Kelvin Kai-Wang; Yuan, Shuofeng; Yuen, Kwok-Yung (2020-01-01). "Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan". Emerging Microbes & Infections 9 (1): 221–236. doi:10.1080/22221751.2020.1719902. ISSN 2222-1751. 
  4. 4.0 4.1 Wang, Changtai; Liu, Zhongping; Chen, Zixiang; Huang, Xin; Xu, Mengyuan; He, Tengfei; Zhang, Zhenhua (2020-03-20). "The establishment of reference sequence for SARS‐CoV‐2 and variation analysis". Journal of Medical Virology 92 (6): 667–674. doi:10.1002/jmv.25762. ISSN 0146-6615. 
  5. 5.0 5.1 Khailany, Rozhgar A.; Safdar, Muhamad; Ozaslan, Mehmet (2020-06). "Genomic characterization of a novel SARS-CoV-2". Gene Reports 19: 100682. doi:10.1016/j.genrep.2020.100682. ISSN 2452-0144. 
  6. Andersen, Kristian G.; Rambaut, Andrew; Lipkin, W. Ian; Holmes, Edward C.; Garry, Robert F. (2020-03-17). "The proximal origin of SARS-CoV-2". Nature Medicine 26 (4): 450–452. doi:10.1038/s41591-020-0820-9. ISSN 1078-8956. 
  7. Li, Yan-Hua; Hu, Chen-Yu; Wu, Nan-Ping; Yao, Hang-Ping; Li, Lan-Juan (2019-10). "Molecular Characteristics, Functions, and Related Pathogenicity of MERS-CoV Proteins". Engineering 5 (5): 940–947. doi:10.1016/j.eng.2018.11.035. ISSN 2095-8099. 
  8. Song, Zhiqi; Xu, Yanfeng; Bao, Linlin; Zhang, Ling; Yu, Pin; Qu, Yajin; Zhu, Hua; Zhao, Wenjie et al. (2019-01-14). "From SARS to MERS, Thrusting Coronaviruses into the Spotlight". Viruses 11 (1): 59. doi:10.3390/v11010059. ISSN 1999-4915. 
  9. Hilgenfeld, Rolf (2014-08-11). "From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design". FEBS Journal 281 (18): 4085–4096. doi:10.1111/febs.12936. ISSN 1742-464X. 
  10. 10.0 10.1 Calligari, Paolo; Bobone, Sara; Ricci, Giorgio; Bocedi, Alessio (2020-04-14). "Molecular Investigation of SARS–CoV-2 Proteins and Their Interactions with Antiviral Drugs". Viruses 12 (4): 445. doi:10.3390/v12040445. ISSN 1999-4915. 
  11. Liu, Ding Xiang; Fung, To Sing; Chong, Kelvin Kian-Long; Shukla, Aditi; Hilgenfeld, Rolf (2014-09). "Accessory proteins of SARS-CoV and other coronaviruses". Antiviral Research 109: 97–109. doi:10.1016/j.antiviral.2014.06.013. ISSN 0166-3542. 
  12. Medhi, Bikash; Prajapat, Manisha; Sarma, Phulen; Shekhar, Nishant; Avti, Pramod; Sinha, Shweta; Kaur, Hardeep; Kumar, Subodh et al. (2020). "Drug for corona virus: A systematic review". Indian Journal of Pharmacology 52 (1): 56. doi:10.4103/ijp.ijp_115_20. ISSN 0253-7613. 
  13. Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan et al. (2020-02-03). "A pneumonia outbreak associated with a new coronavirus of probable bat origin". Nature 579 (7798): 270–273. doi:10.1038/s41586-020-2012-7. ISSN 0028-0836. 
  14. Cagliani, Rachele; Forni, Diego; Clerici, Mario; Sironi, Manuela (2020-04-01). "Computational inference of selection underlying the evolution of the novel coronavirus, SARS-CoV-2". Journal of Virology. doi:10.1128/jvi.00411-20. ISSN 0022-538X. 
  15. Huang, Cheng; Lokugamage, Kumari G.; Rozovics, Janet M.; Narayanan, Krishna; Semler, Bert L.; Makino, Shinji (2011-12-08). "SARS Coronavirus nsp1 Protein Induces Template-Dependent Endonucleolytic Cleavage of mRNAs: Viral mRNAs Are Resistant to nsp1-Induced RNA Cleavage". PLoS Pathogens 7 (12): e1002433. doi:10.1371/journal.ppat.1002433. ISSN 1553-7374. 
  16. 16.0 16.1 Madeira, Fábio; Park, Young mi; Lee, Joon; Buso, Nicola; Gur, Tamer; Madhusoodanan, Nandana; Basutkar, Prasad; Tivey, Adrian R N et al. (2019-04-12). "The EMBL-EBI search and sequence analysis tools APIs in 2019". Nucleic Acids Research 47 (W1): W636–W641. doi:10.1093/nar/gkz268. ISSN 0305-1048. 
  17. Cornillez-Ty, Cromwell T.; Liao, Lujian; Yates, John R.; Kuhn, Peter; Buchmeier, Michael J. (2009-07-29). "Severe Acute Respiratory Syndrome Coronavirus Nonstructural Protein 2 Interacts with a Host Protein Complex Involved in Mitochondrial Biogenesis and Intracellular Signaling". Journal of Virology 83 (19): 10314–10318. doi:10.1128/jvi.00842-09. ISSN 0022-538X. 
  18. 18.0 18.1 Sakai, Yusuke; Kawachi, Kengo; Terada, Yutaka; Omori, Hiroko; Matsuura, Yoshiharu; Kamitani, Wataru (2017-10). "Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication". Virology 510: 165–174. doi:10.1016/j.virol.2017.07.019. ISSN 0042-6822. 
  19. Lei, Jian; Kusov, Yuri; Hilgenfeld, Rolf (2018-01). "Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein". Antiviral Research 149: 58–74. doi:10.1016/j.antiviral.2017.11.001. ISSN 0166-3542. 
  20. Báez-Santos, Yahira M.; St. John, Sarah E.; Mesecar, Andrew D. (2015-03). "The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds". Antiviral Research 115: 21–38. doi:10.1016/j.antiviral.2014.12.015. ISSN 0166-3542. 
  21. Tomar, Sakshi; Johnston, Melanie L.; St. John, Sarah E.; Osswald, Heather L.; Nyalapatla, Prasanth R.; Paul, Lake N.; Ghosh, Arun K.; Denison, Mark R. et al. (2015-06-08). "Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro)". Journal of Biological Chemistry 290 (32): 19403–19422. doi:10.1074/jbc.m115.651463. ISSN 0021-9258. 
  22. Cottam, Eleanor M; Whelband, Matthew C; Wileman, Thomas (2014-06-11). "Coronavirus NSP6 restricts autophagosome expansion". Autophagy 10 (8): 1426–1441. doi:10.4161/auto.29309. ISSN 1554-8627. 
  23. Angelini, Megan M.; Akhlaghpour, Marzieh; Neuman, Benjamin W.; Buchmeier, Michael J. (2013-08-13). "Severe Acute Respiratory Syndrome Coronavirus Nonstructural Proteins 3, 4, and 6 Induce Double-Membrane Vesicles". mBio 4 (4). doi:10.1128/mbio.00524-13. ISSN 2150-7511. 
  24. te Velthuis, Aartjan J.W.; van den Worm, Sjoerd H. E.; Snijder, Eric J. (2011-10-29). "The SARS-coronavirus nsp7+nsp8 complex is a unique multimeric RNA polymerase capable of both de novo initiation and primer extension". Nucleic Acids Research 40 (4): 1737–1747. doi:10.1093/nar/gkr893. ISSN 1362-4962. 
  25. Gao, Yan; Yan, Liming; Huang, Yucen; Liu, Fengjiang; Zhao, Yao; Cao, Lin; Wang, Tao; Sun, Qianqian; Ming, Zhenhua (2020-03-17). "Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target". Retrieved 2020-05-14.
  26. Zhao, Shuangcheng; Ge, Xinna; Wang, Xiaolong; Liu, Aijing; Guo, Xin; Zhou, Lei; Yu, Kangzhen; Yang, Hanchun (2015-01). "The DEAD-box RNA helicase 5 positively regulates the replication of porcine reproductive and respiratory syndrome virus by interacting with viral Nsp9 in vitro". Virus Research 195: 217–224. doi:10.1016/j.virusres.2014.10.021. ISSN 0168-1702. 
  27. Ma, Yuanyuan; Wu, Lijie; Shaw, Neil; Gao, Yan; Wang, Jin; Sun, Yuna; Lou, Zhiyong; Yan, Liming et al. (2015-07-09). "Structural basis and functional analysis of the SARS coronavirus nsp14–nsp10 complex". Proceedings of the National Academy of Sciences 112 (30): 9436–9441. doi:10.1073/pnas.1508686112. ISSN 0027-8424. 
  28. Wang, Yi; Sun, Ying; Wu, Andong; Xu, Shan; Pan, Ruangang; Zeng, Cong; Jin, Xu; Ge, Xingyi et al. (2015-06-03). "Coronavirus nsp10/nsp16 Methyltransferase Can Be Targeted by nsp10-Derived PeptideIn VitroandIn VivoTo Reduce Replication and Pathogenesis". Journal of Virology 89 (16): 8416–8427. doi:10.1128/jvi.00948-15. ISSN 0022-538X. 
  29. Subissi, Lorenzo; Posthuma, Clara C.; Collet, Axelle; Zevenhoven-Dobbe, Jessika C.; Gorbalenya, Alexander E.; Decroly, Etienne; Snijder, Eric J.; Canard, Bruno et al. (2014-09-02). "One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities". Proceedings of the National Academy of Sciences 111 (37): E3900–E3909. doi:10.1073/pnas.1323705111. ISSN 0027-8424. 
  30. Jang, Kyoung-Jin; Jeong, Seonghwan; Kang, Dong Young; Sp, Nipin; Yang, Young Mok; Kim, Dong-Eun (2020-03-11). "A high ATP concentration enhances the cooperative translocation of the SARS coronavirus helicase nsP13 in the unwinding of duplex RNA". Scientific Reports 10 (1). doi:10.1038/s41598-020-61432-1. ISSN 2045-2322. 
  31. Jia, Zhihui; Yan, Liming; Ren, Zhilin; Wu, Lijie; Wang, Jin; Guo, Jing; Zheng, Litao; Ming, Zhenhua et al. (2019-05-27). "Delicate structural coordination of the Severe Acute Respiratory Syndrome coronavirus Nsp13 upon ATP hydrolysis". Nucleic Acids Research 47 (12): 6538–6550. doi:10.1093/nar/gkz409. ISSN 0305-1048. 
  32. 32.0 32.1 Ivanov, Konstantin A.; Thiel, Volker; Dobbe, Jessika C.; van der Meer, Yvonne; Snijder, Eric J.; Ziebuhr, John (2004-06-01). "Multiple Enzymatic Activities Associated with Severe Acute Respiratory Syndrome Coronavirus Helicase". Journal of Virology 78 (11): 5619–5632. doi:10.1128/jvi.78.11.5619-5632.2004. ISSN 0022-538X. 
  33. Case, James Brett; Ashbrook, Alison W.; Dermody, Terence S.; Denison, Mark R. (2016-06-01). "Mutagenesis ofS-Adenosyl-l-Methionine-Binding Residues in Coronavirus nsp14 N7-Methyltransferase Demonstrates Differing Requirements for Genome Translation and Resistance to Innate Immunity". Journal of Virology 90 (16): 7248–7256. doi:10.1128/jvi.00542-16. ISSN 0022-538X. 
  34. Jin, Xu; Chen, Yu; Sun, Ying; Zeng, Cong; Wang, Yi; Tao, Jiali; Wu, Andong; Yu, Xiao et al. (2013-09). "Characterization of the guanine-N7 methyltransferase activity of coronavirus nsp14 on nucleotide GTP". Virus Research 176 (1-2): 45–52. doi:10.1016/j.virusres.2013.05.001. ISSN 0168-1702. 
  35. Bouvet, Mickaël; Debarnot, Claire; Imbert, Isabelle; Selisko, Barbara; Snijder, Eric J.; Canard, Bruno; Decroly, Etienne (2010-04-22). "In Vitro Reconstitution of SARS-Coronavirus mRNA Cap Methylation". PLoS Pathogens 6 (4): e1000863. doi:10.1371/journal.ppat.1000863. ISSN 1553-7374. 
  36. Nakagawa, K.; Lokugamage, K.G.; Makino, S. (2016). Coronaviruses. Elsevier. pp. 165–192. ISBN 978-0-12-804736-1. 
  37. Bhardwaj, Kanchan; Sun, Jingchuan; Holzenburg, Andreas; Guarino, Linda A.; Kao, C. Cheng (2006-08). "RNA Recognition and Cleavage by the SARS Coronavirus Endoribonuclease". Journal of Molecular Biology 361 (2): 243–256. doi:10.1016/j.jmb.2006.06.021. ISSN 0022-2836. 
  38. Hackbart, Matthew; Deng, Xufang; Baker, Susan C. (2020-03-20). "Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors". Proceedings of the National Academy of Sciences 117 (14): 8094–8103. doi:10.1073/pnas.1921485117. ISSN 0027-8424. 
  39. Bhardwaj, Kanchan; Palaninathan, Satheesh; Alcantara, Joanna Maria Ortiz; Li Yi, Lillian; Guarino, Linda; Sacchettini, James C.; Kao, C. Cheng (2007-11-28). "Structural and Functional Analyses of the Severe Acute Respiratory Syndrome Coronavirus Endoribonuclease Nsp15". Journal of Biological Chemistry 283 (6): 3655–3664. doi:10.1074/jbc.m708375200. ISSN 0021-9258. 
  40. 40.0 40.1 Kim, Youngchang; Jedrzejczak, Robert; Maltseva, Natalia I.; Endres, Michael; Godzik, Adam; Michalska, Karolina; Joachimiak, Andrzej (2020-03-03). "Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2". Retrieved 2020-05-14.
  41. Bhardwaj, Kanchan; Guarino, Linda; Kao, C. Cheng (2004-11-15). "The Severe Acute Respiratory Syndrome Coronavirus Nsp15 Protein Is an Endoribonuclease That Prefers Manganese as a Cofactor". Journal of Virology 78 (22): 12218–12224. doi:10.1128/jvi.78.22.12218-12224.2004. ISSN 0022-538X. 
  42. Deng, Xufang; Baker, Susan C. (2018-04). "An “Old” protein with a new story: Coronavirus endoribonuclease is important for evading host antiviral defenses". Virology 517: 157–163. doi:10.1016/j.virol.2017.12.024. ISSN 0042-6822. 
  43. Decroly, Etienne; Imbert, Isabelle; Coutard, Bruno; Bouvet, Mickaël; Selisko, Barbara; Alvarez, Karine; Gorbalenya, Alexander E.; Snijder, Eric J. et al. (2008-04-16). "Coronavirus Nonstructural Protein 16 Is a Cap-0 Binding Enzyme Possessing (Nucleoside-2′O)-Methyltransferase Activity". Journal of Virology 82 (16): 8071–8084. doi:10.1128/jvi.00407-08. ISSN 0022-538X. 
  44. 44.0 44.1 Decroly, Etienne; Debarnot, Claire; Ferron, François; Bouvet, Mickael; Coutard, Bruno; Imbert, Isabelle; Gluais, Laure; Papageorgiou, Nicolas et al. (2011-05-26). "Crystal Structure and Functional Analysis of the SARS-Coronavirus RNA Cap 2′-O-Methyltransferase nsp10/nsp16 Complex". PLoS Pathogens 7 (5): e1002059. doi:10.1371/journal.ppat.1002059. ISSN 1553-7374. 
  45. 45.0 45.1 45.2 45.3 45.4 Walls, Alexandra C.; Park, Young-Jun; Tortorici, M. Alexandra; Wall, Abigail; McGuire, Andrew T.; Veesler, David (2020-02-20). "Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein". Retrieved 2020-05-14.
  46. Gui, Miao; Song, Wenfei; Zhou, Haixia; Xu, Jingwei; Chen, Silian; Xiang, Ye; Wang, Xinquan (2016-12-23). "Cryo-electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conformational state for receptor binding". Cell Research 27 (1): 119–129. doi:10.1038/cr.2016.152. ISSN 1001-0602. 
  47. 47.0 47.1 Wang, X.; Lan, J.; Ge, J.; Yu, J.; Shan, S. (2020-03-18). "Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2". Retrieved 2020-05-14.
  48. Shang, Jian; Ye, Gang; Shi, Ke; Wan, Yushun; Luo, Chuming; Aihara, Hideki; Geng, Qibin; Auerbach, Ashley et al. (2020-03-30). "Structural basis of receptor recognition by SARS-CoV-2". Nature 581 (7807): 221–224. doi:10.1038/s41586-020-2179-y. ISSN 0028-0836. 
  49. Coutard, B.; Valle, C.; de Lamballerie, X.; Canard, B.; Seidah, N.G.; Decroly, E. (2020-04). "The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade". Antiviral Research 176: 104742. doi:10.1016/j.antiviral.2020.104742. ISSN 0166-3542. 
  50. Siu, Kam‐Leung; Yuen, Kit‐San; Castano‐Rodriguez, Carlos; Ye, Zi‐Wei; Yeung, Man‐Lung; Fung, Sin‐Yee; Yuan, Shuofeng; Chan, Chi‐Ping et al. (2019-04-29). "Severe acute respiratory syndrome Coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3‐dependent ubiquitination of ASC". The FASEB Journal 33 (8): 8865–8877. doi:10.1096/fj.201802418r. ISSN 0892-6638. 
  51. Verdiá-Báguena, Carmina; Nieto-Torres, Jose L.; Alcaraz, Antonio; DeDiego, Marta L.; Torres, Jaume; Aguilella, Vicente M.; Enjuanes, Luis (2012-10). "Coronavirus E protein forms ion channels with functionally and structurally-involved membrane lipids". Virology 432 (2): 485–494. doi:10.1016/j.virol.2012.07.005. ISSN 0042-6822. 
  52. Schoeman, Dewald; Fielding, Burtram C. (2019-05-27). "Coronavirus envelope protein: current knowledge". Virology Journal 16 (1). doi:10.1186/s12985-019-1182-0. ISSN 1743-422X. 
  53. Lim, K. P.; Liu, D. X. (2001-02-08). "The Missing Link in Coronavirus Assembly". Journal of Biological Chemistry 276 (20): 17515–17523. doi:10.1074/jbc.m009731200. ISSN 0021-9258. 
  54. Ruch, Travis R.; Machamer, Carolyn E. (2012-03-08). "The Coronavirus E Protein: Assembly and Beyond". Viruses 4 (3): 363–382. doi:10.3390/v4030363. ISSN 1999-4915. 
  55. Weiss, Susan R.; Navas-Martin, Sonia (2005-12). "Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus". Microbiology and Molecular Biology Reviews 69 (4): 635–664. doi:10.1128/mmbr.69.4.635-664.2005. ISSN 1092-2172. 
  56. Neuman, Benjamin W.; Kiss, Gabriella; Kunding, Andreas H.; Bhella, David; Baksh, M. Fazil; Connelly, Stephen; Droese, Ben; Klaus, Joseph P. et al. (2011-04). "A structural analysis of M protein in coronavirus assembly and morphology". Journal of Structural Biology 174 (1): 11–22. doi:10.1016/j.jsb.2010.11.021. ISSN 1047-8477. 
  57. Tsoi, Ho; Li, Li; Chen, Zhefan S.; Lau, Kwok-Fai; Tsui, Stephen K. W.; Chan, Ho Yin Edwin (2014-12-05). "The SARS-coronavirus membrane protein induces apoptosis via interfering with PDK1–PKB/Akt signalling". Biochemical Journal 464 (3): 439–447. doi:10.1042/bj20131461. ISSN 0264-6021. 
  58. Siu, Y. L.; Teoh, K. T.; Lo, J.; Chan, C. M.; Kien, F.; Escriou, N.; Tsao, S. W.; Nicholls, J. M. et al. (2008-08-27). "The M, E, and N Structural Proteins of the Severe Acute Respiratory Syndrome Coronavirus Are Required for Efficient Assembly, Trafficking, and Release of Virus-Like Particles". Journal of Virology 82 (22): 11318–11330. doi:10.1128/jvi.01052-08. ISSN 0022-538X. 
  59. Kumar, Purnima; Gunalan, Vithiagaran; Liu, Boping; Chow, Vincent T.K.; Druce, Julian; Birch, Chris; Catton, Mike; Fielding, Burtram C. et al. (2007-09). "The nonstructural protein 8 (nsp8) of the SARS coronavirus interacts with its ORF6 accessory protein". Virology 366 (2): 293–303. doi:10.1016/j.virol.2007.04.029. ISSN 0042-6822. 
  60. Zhao, Jincun; Falcón, Ana; Zhou, Haixia; Netland, Jason; Enjuanes, Luis; Pérez Breña, Pilar; Perlman, Stanley (2008-12-17). "Severe Acute Respiratory Syndrome Coronavirus Protein 6 Is Required for Optimal Replication". Journal of Virology 83 (5): 2368–2373. doi:10.1128/jvi.02371-08. ISSN 0022-538X. 
  61. 61.0 61.1 Nelson, Christopher A.; Pekosz, Andrew; Lee, Chung A.; Diamond, Michael S.; Fremont, Daved H. (2005-01). "Structure and Intracellular Targeting of the SARS-Coronavirus Orf7a Accessory Protein". Structure 13 (1): 75–85. doi:10.1016/j.str.2004.10.010. ISSN 0969-2126. 
  62. Schaecher, Scott R.; Mackenzie, Jason M.; Pekosz, Andrew (2006-11-01). "The ORF7b Protein of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Is Expressed in Virus-Infected Cells and Incorporated into SARS-CoV Particles". Journal of Virology 81 (2): 718–731. doi:10.1128/jvi.01691-06. ISSN 0022-538X. 
  63. Le, Tra M.; Wong, Hui H.; Tay, Felicia P. L.; Fang, Shouguo; Keng, Choong-Tat; Tan, Yee J.; Liu, Ding X. (2007-07-20). "Expression, post-translational modification and biochemical characterization of proteins encoded by subgenomic mRNA8 of the severe acute respiratory syndrome coronavirus". FEBS Journal 274 (16): 4211–4222. doi:10.1111/j.1742-4658.2007.05947.x. ISSN 1742-464X. 
  64. Wong, Hui Hui; Fung, To Sing; Fang, Shouguo; Huang, Mei; Le, My Tra; Liu, Ding Xiang (2018-02). "Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3". Virology 515: 165–175. doi:10.1016/j.virol.2017.12.028. ISSN 0042-6822. 
  65. Grunewald, Matthew E.; Fehr, Anthony R.; Athmer, Jeremiah; Perlman, Stanley (2018-04). "The coronavirus nucleocapsid protein is ADP-ribosylated". Virology 517: 62–68. doi:10.1016/j.virol.2017.11.020. ISSN 0042-6822. 
  66. Mu, Jingfang; Xu, Jiuyue; Zhang, Leike; Shu, Ting; Wu, Di; Huang, Muhan; Ren, Yujie; Li, Xufang et al. (2020-04-10). "SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells". Science China Life Sciences. doi:10.1007/s11427-020-1692-1. ISSN 1674-7305. 
  67. Surjit, Milan; Liu, Boping; Chow, Vincent T. K.; Lal, Sunil K. (2006-01-23). "The Nucleocapsid Protein of Severe Acute Respiratory Syndrome-Coronavirus Inhibits the Activity of Cyclin-Cyclin-dependent Kinase Complex and Blocks S Phase Progression in Mammalian Cells". Journal of Biological Chemistry 281 (16): 10669–10681. doi:10.1074/jbc.m509233200. ISSN 0021-9258. 
  68. 68.0 68.1 Gordon, David E.; Jang, Gwendolyn M.; Bouhaddou, Mehdi; Xu, Jiewei; Obernier, Kirsten; White, Kris M.; O’Meara, Matthew J.; Rezelj, Veronica V. et al. (2020-04-30). "A SARS-CoV-2 protein interaction map reveals targets for drug repurposing". Nature. doi:10.1038/s41586-020-2286-9. ISSN 0028-0836. 
  69. Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.; Couch, Gregory S.; Greenblatt, Daniel M.; Meng, Elaine C.; Ferrin, Thomas E. (2004). "UCSF Chimera?A visualization system for exploratory research and analysis". Journal of Computational Chemistry 25 (13): 1605–1612. doi:10.1002/jcc.20084. ISSN 0192-8651. 
  70. Schroeder, M.; Ni, X.; Olieric, V.; Sharpe, E.M.; Wojdyla, J.A.; Wang, M.; Knapp, S.; Chaikuad, A. (2020-05-06). "Crystal structure of SARS-CoV-2 (Covid-19) NSP3 macrodomain in complex with ADP-ribose". doi:10.2210/pdb6ywl/pdb. Retrieved 2020-05-14.
  71. Osipiuk, J.; Jedrzejczak, R.; Tesar, C.; Endres, M.; Stols, L.; Babnigg, G.; Kim, Y.; Michalska, K.; Joachimiak, A. (2020-04-01). "The crystal structure of papain-like protease of SARS CoV-2". doi:10.2210/pdb6w9c/pdb. Retrieved 2020-05-14.
  72. Su, H.X.; Zhao, W.F.; Li, M.J.; Xie, H.; Xu, Y.C. (2020-04-15). "SARS-CoV-2 3CL protease (3CL pro) in complex with a novel inhibitor". doi:10.2210/pdb6m2n/pdb. Retrieved 2020-05-14.
  73. Zhang, Linlin; Lin, Daizong; Sun, Xinyuanyuan; Curth, Ute; Drosten, Christian; Sauerhering, Lucie; Becker, Stephan; Rox, Katharina et al. (2020-03-20). "Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors". Science: eabb3405. doi:10.1126/science.abb3405. ISSN 0036-8075. 
  74. Kim, Y.; Wilamowski, M.; Jedrzejczak, R.; Maltseva, N.; Endres, M.; Godzik, A.; Michalska, K.; Joachimiak, A. (2020-05-06). "The 1.95 A Crystal Structure of the Co-factor Complex of NSP7 and the C-terminal Domain of NSP8 from SARS-CoV-2". doi:10.2210/pdb6wqd/pdb. Retrieved 2020-05-14.
  75. Tan, K.; Kim, Y.; Jedrzejczak, R.; Maltseva, N.; Endres, M.; Michalska, K.; Joachimiak, A. (2020-03-18). "The crystal structure of Nsp9 RNA binding protein of SARS CoV-2". doi:10.2210/pdb6w4b/pdb. Retrieved 2020-05-14.
  76. 76.0 76.1 Yin, Wanchao; Mao, Chunyou; Luan, Xiaodong; Shen, Dan-Dan; Shen, Qingya; Su, Haixia; Wang, Xiaoxi; Zhou, Fulai et al. (2020-05-01). "Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir". Science. doi:10.1126/science.abc1560. ISSN 0036-8075. PMID 32358203. PMC 7199908. 
  77. Minasov, G.; Shuvalova, L.; Rosas-Lemus, M.; Brunzelle, J.S.; Kiryukhina, O.; Satchell, K.J.F. (2020-05-06). "Crystal Structure of Nsp16-Nsp10 Heterodimer from SARS-CoV-2 in Complex with 7-methyl-GpppA and S-adenosyl-L-homocysteine". doi:10.2210/pdb6wq3/pdb. Retrieved 2020-05-14.
  78. Minasov, G.; Shuvalova, L.; Rosas-Lemus, M.; Kiryukhina, O.; Satchell, K.J.F. (2020-04-29). "1.98 Angstrom Resolution Crystal Structure of NSP16-NSP10 Heterodimer from SARS-CoV-2 in Complex with Sinefungin". doi:10.2210/pdb6WKQ/pdb. Retrieved 2020-05-14.
  79. Nelson, C.A.; Fremont, D.H. (2020-04-29). "Structure of the SARS-CoV-2 ORF7a encoded accessory protein". doi:10.2210/pdb6w37/pdb. Retrieved 2020-05-14.
  80. Minasov, G.; Shuvalova, L.; Wiersum, G.; Satchell, K.J.F. (2020-04-22). "2.05 Angstrom Resolution Crystal Structure of C-terminal Dimerization Domain of Nucleocapsid Phosphoprotein from SARS-CoV-2". doi:10.2210/pdb6wji/pdb. Retrieved 2020-05-14.
  81. Rancurel, Corinne; Khosravi, Mahvash; Dunker, A. Keith; Romero, Pedro R.; Karlin, David (2009-07-29). "Overlapping Genes Produce Proteins with Unusual Sequence Properties and Offer Insight into De Novo Protein Creation". Journal of Virology 83 (20): 10719–10736. doi:10.1128/jvi.00595-09. ISSN 0022-538X. 
  82. Shukla, Aditi; Hilgenfeld, Rolf (2014-11-20). "Acquisition of new protein domains by coronaviruses: analysis of overlapping genes coding for proteins N and 9b in SARS coronavirus". Virus Genes 50 (1): 29–38. doi:10.1007/s11262-014-1139-8. ISSN 0920-8569. 
  83. Wu, Aiping; Peng, Yousong; Huang, Baoying; Ding, Xiao; Wang, Xianyue; Niu, Peihua; Meng, Jing; Zhu, Zhaozhong et al. (2020-03). "Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China". Cell Host & Microbe 27 (3): 325–328. doi:10.1016/j.chom.2020.02.001. ISSN 1931-3128. 
  84. Jean, Shio-Shin; Lee, Ping-Ing; Hsueh, Po-Ren (2020-04). "Treatment options for COVID-19: The reality and challenges". Journal of Microbiology, Immunology and Infection. doi:10.1016/j.jmii.2020.03.034. ISSN 1684-1182. 
  85. Costanzo, Michele; De Giglio, Maria Anna Rachele; Roviello, Giovanni Nicola (2020-04-16). "SARS CoV-2: Recent Reports on Antiviral Therapies Based on Lopinavir/Ritonavir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and Other Drugs for the Treatment of the New Coronavirus". Current Medicinal Chemistry 27. doi:10.2174/0929867327666200416131117. ISSN 0929-8673. 
  86. Zeng, Qing-Lei; Yu, Zu-Jiang; Gou, Jian-Jun; Li, Guang-Ming; Ma, Shu-Huan; Zhang, Guo-Fan; Xu, Jiang-Hai; Lin, Wan-Bao et al. (2020-04-29). "Effect of Convalescent Plasma Therapy on Viral Shedding and Survival in COVID-19 Patients". The Journal of Infectious Diseases. doi:10.1093/infdis/jiaa228. ISSN 0022-1899. 
  87. Caly, Leon; Druce, Julian D.; Catton, Mike G.; Jans, David A.; Wagstaff, Kylie M. (2020-06). "The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro". Antiviral Research 178: 104787. doi:10.1016/j.antiviral.2020.104787. ISSN 0166-3542. 
  88. Fu, Bao; Qian, Kun; Fu, Xiaoyun (2020-04). "Pre- and post-treatment chest CT changes in a patient with COVID-19". Medicina Clínica. doi:10.1016/j.medcli.2020.04.005. ISSN 0025-7753. 
  89. Kupferschmidt, Kai; Cohen, Jon (2020-03-26). "Race to find COVID-19 treatments accelerates". Science 367 (6485): 1412–1413. doi:10.1126/science.367.6485.1412. ISSN 0036-8075. 
  90. Siegel, Dustin; Hui, Hon C.; Doerffler, Edward; Clarke, Michael O.; Chun, Kwon; Zhang, Lijun; Neville, Sean; Carra, Ernest et al. (2017-01-26). "Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f[triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses"]. Journal of Medicinal Chemistry 60 (5): 1648–1661. doi:10.1021/acs.jmedchem.6b01594. ISSN 0022-2623. 
  91. Gordon, Calvin J; Tchesnokov, Egor P; Woolner, Emma; Perry, Jason K; Feng, Joy Y.; Porter, Danielle P; Gotte, Matthias (2020-04-13). "Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency". Journal of Biological Chemistry: jbc.RA120.013679. doi:10.1074/jbc.ra120.013679. ISSN 0021-9258. 
  92. Meyerowitz, Eric A.; Vannier, Augustin G. L.; Friesen, Morgan G. N.; Schoenfeld, Sara; Gelfand, Jeffrey A.; Callahan, Michael V.; Kim, Arthur Y.; Reeves, Patrick M. et al. (2020-04-29). "Rethinking the role of hydroxychloroquine in the treatment of COVID‐19". The FASEB Journal 34 (5): 6027–6037. doi:10.1096/fj.202000919. ISSN 0892-6638. 
  93. Touret, Franck; de Lamballerie, Xavier (2020-05). "Of chloroquine and COVID-19". Antiviral Research 177: 104762. doi:10.1016/j.antiviral.2020.104762. ISSN 0166-3542. 
  94. Wong, Yin Kwan; Yang, Jing; He, Yingke (2020-05). "Caution and clarity required in the use of chloroquine for COVID-19". The Lancet Rheumatology 2 (5): e255. doi:10.1016/s2665-9913(20)30093-x. ISSN 2665-9913. 
  95. Joyce, Emer; Fabre, Aurelie; Mahon, Niall (2012-12-19). "Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review". European Heart Journal: Acute Cardiovascular Care 2 (1): 77–83. doi:10.1177/2048872612471215. ISSN 2048-8726. 
  96. Geleris, Joshua; Sun, Yifei; Platt, Jonathan; Zucker, Jason; Baldwin, Matthew; Hripcsak, George; Labella, Angelena; Manson, Daniel et al. (2020-05-07). "Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19". New England Journal of Medicine. doi:10.1056/nejmoa2012410. ISSN 0028-4793. 
  97. Xu, Jia; Zhang, Yunfei (2020-05). "Traditional Chinese Medicine treatment of COVID-19". Complementary Therapies in Clinical Practice 39: 101165. doi:10.1016/j.ctcp.2020.101165. ISSN 1744-3881. 
  98. Chen, C.-H.; Dickman, K. G.; Moriya, M.; Zavadil, J.; Sidorenko, V. S.; Edwards, K. L.; Gnatenko, D. V.; Wu, L. et al. (2012-04-09). "Aristolochic acid-associated urothelial cancer in Taiwan". Proceedings of the National Academy of Sciences 109 (21): 8241–8246. doi:10.1073/pnas.1119920109. ISSN 0027-8424. 
  99. Duan, Li; Guo, Long; Wang, Lei; Yin, Qiang; Zhang, Chen-Meng; Zheng, Yu-Guang; Liu, E.-Hu (2018-12). "Application of metabolomics in toxicity evaluation of traditional Chinese medicines". Chinese Medicine 13 (1). doi:10.1186/s13020-018-0218-5. ISSN 1749-8546. 
  100. Lv, Wen; Piao, Jin-Hua; Jiang, Jian-Guo (2012-09-19). "Typical toxic components in traditional Chinese medicine". Expert Opinion on Drug Safety 11 (6): 985–1002. doi:10.1517/14740338.2012.726610. ISSN 1474-0338. 
  101. Wassenaar, T.M.; Zou, Y. (2020-05). "2019_nCoV/SARS‐CoV‐2: rapid classification of betacoronaviruses and identification of Traditional Chinese Medicine as potential origin of zoonotic coronaviruses". Letters in Applied Microbiology 70 (5): 342–348. doi:10.1111/lam.13285. ISSN 0266-8254. 
  102. Lurie, Nicole; Saville, Melanie; Hatchett, Richard; Halton, Jane (2020-03-30). "Developing Covid-19 Vaccines at Pandemic Speed". New England Journal of Medicine. doi:10.1056/nejmp2005630. ISSN 0028-4793. 
  103. Brown, Bethany L.; McCullough, Jeffrey (2020-04). "Treatment for emerging viruses: Convalescent plasma and COVID-19". Transfusion and Apheresis Science: 102790. doi:10.1016/j.transci.2020.102790. ISSN 1473-0502. 
  104. Xu, Shunqing; Li, Yuanyuan (2020-04). "Beware of the second wave of COVID-19". The Lancet 395 (10233): 1321–1322. doi:10.1016/s0140-6736(20)30845-x. ISSN 0140-6736. 
  105. Leung, Kathy; Wu, Joseph T; Liu, Di; Leung, Gabriel M (2020-04). "First-wave COVID-19 transmissibility and severity in China outside Hubei after control measures, and second-wave scenario planning: a modelling impact assessment". The Lancet 395 (10233): 1382–1393. doi:10.1016/s0140-6736(20)30746-7. ISSN 0140-6736. 
  106. Ceraolo, Carmine; Giorgi, Federico M. (2020-05). "Genomic variance of the 2019‐nCoV coronavirus". Journal of Medical Virology 92 (5): 522–528. doi:10.1002/jmv.25700. ISSN 0146-6615. 
  107. "Severe acute respiratory syndrome coronavirus 2". Retrieved 2020-04-26.