Figure 5. The potential mechanism of SARS-CoV-2 inducing
cytokine storm.
- Treatment strategy of COVID-19
- 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.