Molecular Basics of Transmission of Coronavirus
In case of SARS-CoV, transmission is through droplet infection (respiratory secretions) and close person-to-person contact.[1112] It can also spread through sweat, stool, urine, and respiratory secretions.[13] When virus enters into the body, it binds to the primary target cells such as enterocytes and pneumocytes,[1112] thereby establishing a cycle of infection and replication. Other target cells of CoV are epithelial renal tubules, tubular epithelial cells of kidney, immune cells, and cerebral neuronal cells.[1112]
CoV attaches to the target cells with the help of spike protein–host cell protein interaction (angiotensin converting enzyme-2 [ACE-2] interaction in SARS-CoV[14] and dipeptidyl peptidase-4 [DPP-4] in MERS-CoV[15]). After the receptor recognition, the virus genome with its nucleocapsid is released into the cytoplasm of the host cells. The viral genome contains ORF1a and ORF1b genes, which produce two PPs that are pp1a and pp1b,[16] which help to take command over host ribosomes for their own translation process.[17] Both pp1a and pp1b take part in the formation of the replication transcription complex.[16] After processing of PP by protease, it produces 16 NSPs. All NSPs have their own specific functions such as suppression of host gene expression by NSP1 and NSP2, formation of a multidomain complex by NSP3, NSP5 which is a M protease which has role in replication,[17] NSP4 and NSP6 which are transmembrane (TM) proteins,[18] NSP7 and NSP8 which act as a primase,[16] NSP9 – a RNA-binding protein, the dimeric form of which is important for viral infection. Induction of disturbance to the dimerization of NSP9[19] can be a way to overcome CoV infection.[20] NSP10 acts as a cofactor for the activation of the replicative enzyme.[21] NSP12 shows RNA-dependent RNA polymerase activity, NSP13 shows helicase activity, NSP14 shows exoribonuclease activity, NSP15 shows endoribonuclease activity, and NSP16 has methyltransferase activity.[18] All NSPs have an important role in replication and transcription.[18]
Synthesized proteins such as M, E, and S are entered into the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) complex and make the structure of viral envelope.[22] On the other hand, the replicated genome binds to N protein and forms the ribonucleoprotein (RNP) complex. The outer cover is formed by the M, E, and S proteins.[22] Finally, the virus particle comes out of the ERGIC by making a bud-like structure.[23] These mature virions form a vesicle, which fuses with the plasma membrane and releases the virus particles into the extracellular region.[2324] The detailed structure of CoV and its life cycle is depicted in Figures 1 and 2. On infection, the SARS-CoV and MERS-COV cause a surge of pro-inflammatory cytokines and chemokines, which cause damage to lung tissue,[13] deterioration of lung function, and then finally lung failure in some cases.[25]
Figure 1  Structural details of Coronavirus
Figure 2  The life cycle of CoV in host cells. The S proteins of CoV binds to cellular receptor angiotensin-converting enzyme 2 (ACE2) which is followed by entry of the viral RNA genome into the host cell and translation of structural and non structural proteins (NSP) follows. ORF1a and ORF1ab are translated to produce pp1a and pp1ab polyproteins, which are cleaved by the proteases that are encoded by ORF1a to yield 16 non-structural proteins. This is followed by assembly and budding into the lumen of the ERGIC (Endoplasmic Reticulum Golgi Intermediate Compartment). Virions are then released from the infected cell through exocytosis. S: spike, E: envelope, M: membrane, N: nucleocapsid. PP: polyproteins, ORF: Open reading frame, CoV: coronavirus Currently, there is no specific antiviral drug for the treatment of CoV-associated pathologies. Most treatment strategies focus on symptomatic management and supportive therapy only.[2627] Some therapeutic agents that are under development or being used off-label are ribavirin, interferon (IFN)-α, and mycophenolic acid.[7] There are many newspaper articles citing effectiveness of anti-HIV drugs: ritonavir,[2829] lopinavir,[29] either alone or in combination with oseltamivir,[29] remdesivir, and chloroquine;[28] and among these, ritonavir, remdesivir, and chloroquine showed efficacy at cellular level[28] which further need experimental support and validation.
As there is no well-defined therapy available, which specifically targets CoV, in this article, we have reviewed the possible protein structures, which could be potential targets for the development of a therapeutic approach for the treatment of CoV.