Figure 5. The potential mechanism of SARS-CoV-2 inducing cytokine storm.
  1. Treatment strategy of COVID-19
  2. Crucial SARS-CoV-2 targets for novel drug development
The preceding overview of the virology of SARS-CoV-2, as well as the sundry potential mechanisms of damage to the host, lay the foundation for developing specific targeted treatment and prevention. A general idea of pivotal targets for drug discovery is shown in Figure 6. In consideration of the role of the surface structural S in the virus-cell receptor interplay, it is of particular interest for the antiviral development. mAbs against the S1 subunit RBD and fusion inhibitors targeting the S2 subunit possess potential anti-SARS-CoV-2 capacityin vitro or in vivo (Yuan et al., 2004). Besides, since ACE2 is the key functional host receptor of SARS-CoV-2 to determine the pathogenicity, mAbs, or molecules targeting the host receptor are effective anti- SARS-CoV-2 drugs, as long as they do not elicit immunopathological effects in animal models (Zumla et al., 2016). A recent study also probed into the COVID-19 S protein-binding site to the cell-surface receptor (known as Glucose Regulated Protein 78 (GRP78)). Their outcomes unveiled that the binding between regions III and IV of the S protein model and GRP78 was more favorable. In this regard, region IV is the major tractive force for GRP78 binding, and these 9 residues can be leveraged to design therapeutics specific against this disease (Ibrahim et al., 2020). Of note, although inhibitors of the proteases that prime S for fusion possess antiviral activity, multiple inhibitors are needed because S can utilize a variety of proteases for priming (Sun et al., 2020). In addition, agents directly targeting the highly conserved S2 subunit may be potential treatment candidates.
For SARS-CoV-2, the large replicase polyprotein 1a (pp1a) and pp1ab encoded by the ORF1a/b are subjected to two viral proteases, papain-like protease (PLpro) and 3C cleavage-like protease (3CLpro) (also known as Mpro), for producing non-structural proteins (i.e., RdRp, helicases) which are correlated to viral transcription and replication (Figure 3) (Zumla et al., 2016). Therefore, enzyme inhibitors targeting these proteins may exhibit anti-SARS-CoV-2 activity in vitro . A recent study has uncovered that the Mpro of SARS-CoV-2, which is the translated polyproteins of ORF 1a/b, is a crucial enzyme that mediates viral replication and transcription (Dai et al., 2020). Specifically, a Gln residue almost always requires a substrate at P1 (an amino acid in substrates). There is currently no human homologous for Mpro, which makes it a promising antiviral target (Figure 6) (Yang et al., 2005). Dai and coworkers had conducted the structure-based design of antiviral agents targeting this protease by parsing out the substrate-binding pocket of Mpro (Dai et al., 2020). In this regard, further study targeting such a protease may give rise to certain antiviral drug candidates.
Another notable drug target may be the cellular enzymes that attach fatty acids to a cluster of cysteines in the cytoplasmic tail of S due to the fact that fatty acids are essential for the fusion of host cell and assembly of the virus, like the description of other S proteins, such as hemagglutinin for influenza viruses. The enzyme that connects the acyl chain to S has not yet been discovered, but the cellular protein will undergo acetylation by the members from the ZDHHC family with unique, only partially overlapping substrate specificities. If a few of them may be acetylated in the airway cells of the lungs, their blockage may suppress the viral replication, and the acylation of cellular proteins will rarely be damaged. In this regard, targeting acyltransferases may be promising, because the cysteine group is existed in all CoV genus S, in spite of their source (Gadalla and Veit, 2020). However, in consideration of the palmitoylation of crucial proteins in the innate immunity, if the proteins of the innate immune response are modified with the same enzymes as viral proteins, the acylation inhibitor may be limited.