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A Summary of Viral Targets and Recently Released PDB IDs of SARS-CoV-2
Drug discovery and development against coronavirus disease 2019 (COVID-19) is the utmost need and the most challenging task of the hour. Many research groups from different countries are working continuously in this direction, and till 8th March 2020, a total of 382 clinical trials have been registered on the WHO’s International Clinical Trials Registry Platform [1Oxford COVID-19 Evidence Service. https://www.cebm.net/covid-19
/registered-trials-and-analysis]. There is an urgent need to identify specific targets to design promising therapeutic agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. Analysis of SARS-CoV-2 reveals seven major target proteins that can be considered for drug design against the virus. These include the spike, envelope, membrane, nucleocapsid, protease, hemagglutinin esterase and helicase [2Prajapat M, Sarma P, Shekhar N, et al. Drug targets for corona virus: A systematic review. Indian J Pharmacol 2020; 52(1): 56-65. [http://dx.doi.org/10.4103/ijp.IJP_115_20] [PMID: 32201449] , 3Hilgenfeld R. From SARS to MERS: Crystallographic studies on coronaviral proteases enable antiviral drug design. FEBS J 2014; 281(18): 4085-96. [http://dx.doi.org/10.1111/febs.12936] [PMID: 25039866] ]. Beyond these, several Non Structural Proteins (NSPs) can also be evaluated as targets for drug development [4Wang H, Xue S, Yang H, Chen C. Recent progress in the discovery of inhibitors targeting coronavirus proteases. Virol Sin 2016; 31(1): 24-30. [http://dx.doi.org/10.1007/s12250-015-3711-3] [PMID: 26920707] ]. There are only a few Protein Data Bank (PDB) Ids available related to SARS-CoV-2 in the RCSB database. Table 1 summarizes recently released PDB Ids (from 5.2.2020 to 25.3.2020) for various SARS-CoV-2 targets [5Protein Data Bank. www.rcsb.org].
The SARS-CoV-2 genome encodes a relatively large number of proteins [6Jo S, Kim S, Shin DH, Kim MS. Inhibition of SARS-CoV 3CL protease by flavonoids. J Enzyme Inhib Med Chem 2020; 35(1): 145-51. [http://dx.doi.org/10.1080/14756366.2019.1690480] [PMID: 31724441] ]. The PL proteinase and the 3CL protease cleave two polyproteins to release different types of NSPs. Hence the proteases represent a relevant target for designing drugs against SARS-CoV-2. The spike (S) protein helps the virus to enter inside the host and also activates the immune response of the host against the virus through the interaction mediated by its specific segments [7Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol 2016; 3(1): 237-61. [http://dx.doi.org/10.1146/annurev-virology-110615-042301] [PMID: 27578435] ]. Thus, the S protein represents an ideal target for therapeutic drug development. The envelope protein is the smallest protein of SARS-CoV-2 and plays a significant role in morphogenesis of virus particles [8Kuo L, Hurst KR, Masters PS. Exceptional flexibility in the sequence requirements for coronavirus small envelope protein function. J Virol 2007; 81(5): 2249-62. [http://dx.doi.org/10.1128/JVI.01577-06] [PMID: 17182690] ]. It is also reported that the oligomerization of these proteins leads to the formation of specific ion-channels whose role is still unclear. Beyond this, the envelop protein helps in viral assembly and budding, hence its significant as a drug target [9Venkatagopalan P, Daskalova SM, Lopez LA, Dolezal KA, Hogue BG. Coronavirus envelope (E) protein remains at the site of assembly. Virology 2015; 478: 75-85. [http://dx.doi.org/10.1016/j.virol.2015.02.005] [PMID: 25726972] ]. Membrane proteins maintain the shape of a viral envelope [10Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J 2019; 16(1): 69. [http://dx.doi.org/10.1186/s12985-019-1182-0] [PMID: 31133031] ] and also sensitize the host against the virus [11Wang Y, Liu L. The membrane protein of severe acute respiratory syndrome coronavirus functions as a novel cytosolic pathogen-associated molecular pattern to promote beta interferon induction via a toll-like-receptor-related TRAF3-independent mechanism. MBio 2016; 7(1): e01872-15. [http://dx.doi.org/10.1128/mBio.01872-15] [PMID: 26861016] ]. These proteins can also be considered as significant targets for drug development. The nucleocapsid proteins have a structure comprising arm, central linker and tail domains [12Chang CK, Lo SC, Wang YS, Hou MH. Recent insights into the development of therapeutics against coronavirus diseases by targeting N protein. Drug Discov Today 2016; 21(4): 562-72. [http://dx.doi.org/10.1016/j.drudis.2015.11.015] [PMID: 26691874] ]. The main function of these proteins is to form ribonucleoprotein complexes. It also regulates replication, transcription of viral RNA and in the host cells, inhibits protein translation leading to disruption in the host cell metabolism [13J Alsaadi EA, Jones IM. Membrane binding proteins of coronaviruses. Future Virol 2019; 14(4): 275-86. [http://dx.doi.org/10.2217/fvl-2018-0144] [PMID: 32201500] , 14Zhou B, Liu J, Wang Q, et al. The nucleocapsid protein of severe acute respiratory syndrome coronavirus inhibits cell cytokinesis and proliferation by interacting with translation elongation factor 1alpha. J Virol 2008; 82(14): 6962-71. [http://dx.doi.org/10.1128/JVI.00133-08] [PMID: 18448518] ]. Therefore, targeting this protein can lead to blockbuster therapeutic agents for COVID-19 treatment. Hemagglutinin esterase has been established as a marker for the evolution of SARS-CoV-2 or some influenza infections and has the capacity to act as lectins or receptor destroying enzymes [15Zeng Q, Langereis MA, van Vliet AL, Huizinga EG, de Groot RJ. Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution. Proc Natl Acad Sci USA 2008; 105(26): 9065-9. [http://dx.doi.org/10.1073/pnas.0800502105] [PMID: 18550812] ]. The Helicase enzyme is also an interesting target, but its inhibitors are associated with some toxicity and specificity issues [16Frick DN, Lam AM. Understanding helicases as a means of virus control. Curr Pharm Des 2006; 12(11): 1315-38. [http://dx.doi.org/10.2174/138161206776361147] [PMID: 16611118] ].
COVID-19 pandemic has now become a destructive ailment globally. Therefore the utmost need of the hour is to develop therapeutic candidates or vaccines against it. The targets explained in this summary may be of some aid to design novel molecules by employing drug discovery strategies such as artificial intelligence or CADD tools.
Table 1 Recently Released Targets in RCSB Database with PDB Ids related to COVID-19 [5Protein Data Bank. www.rcsb.org].
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
Wang Y, Liu L. The membrane protein of severe acute respiratory syndrome coronavirus functions as a novel cytosolic pathogen-associated molecular pattern to promote beta interferon induction via a toll-like-receptor-related TRAF3-independent mechanism. MBio 2016; 7(1): e01872-15. [http://dx.doi.org/10.1128/mBio.01872-15] [PMID: 26861016]
Zhou B, Liu J, Wang Q, et al. The nucleocapsid protein of severe acute respiratory syndrome coronavirus inhibits cell cytokinesis and proliferation by interacting with translation elongation factor 1alpha. J Virol 2008; 82(14): 6962-71. [http://dx.doi.org/10.1128/JVI.00133-08] [PMID: 18448518]
Zeng Q, Langereis MA, van Vliet AL, Huizinga EG, de Groot RJ. Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution. Proc Natl Acad Sci USA 2008; 105(26): 9065-9. [http://dx.doi.org/10.1073/pnas.0800502105] [PMID: 18550812]