5.2 Drug discovery approaches toward anti-SARS-CoV-2 drug
screening
The drug discovery strategy bears the brunt of the COVID-19 outbreak is
the test of existing broad-spectrum antiviral agents that have been
harnessed to cure other viral infections via utilizing standard tests
for measuring the effects of drugs on the cytopathy, virus production
along with plaque generation in live and pseudotyped CoVs. Drug
discovery utilizing this method encompass interferon α, interferon β,
interferon γ, arbidol, ribavirin, along with cyclophilin inhibitors
(Cheng et al., 2007; Khamitov et al., 2008). These drugs possess the
distinct preponderance of easy access to known pharmacokinetic and
pharmacodynamic features, dose regimens, and adverse effects (Cinatl et
al., 2003). Nevertheless, they have no specific anti-SARS-CoV-2 effect
and may be correlated with severe untoward effects.
In addition to the test of existing broad-spectrum antiviral agents,
another anti-SARS-CoV-2 drug discovery approach might be the chemical
libraries screening, which involves a good deal of existing compounds or
databases with the information on transcriptional signatures in
disparate cell lines (Dyall et al., 2014; Kindrachuk et al., 2015). Such
a method holds the potential of offering a prompt, high-throughput
screening of many off-the-shelf composites, which can thereby be further
assessed via antiviral detection test. Importantly, a variety of
different types of agents have been discovered among these agent
repurposing programs, incorporating many that with significant
physiological and immune effects (i.e., those affecting the lipid or
sterol metabolism, regulation of neurotransmitters, kinase signaling,
estrogen receptors, and DNA synthesis/repair) (Elshabrawy et al., 2014;
de Wilde et al., 2014). It is noteworthy that this method has the main
drawback that most agents are not clinically useful in virtue of their
underlying immunosuppressive effects or anti-SARS-CoV-2 half-maximal
effective concentration values that significantly surpass the peak serum
concentration levels that are obtainable at the therapeutic dose (Que et
al., 2003). An interesting exception is the anti-HIV protease inhibitor
lopinavir-ritonavir, which has been reported to be effective for
SARS-CoV in both non-human primate models and in non-randomized clinical
trials (Chu et al., 2004). In addition, nelfinavir, a selective
inhibitor of HIV protease, which has been demonstrated to possess a
sound suppresion of SARS-CoV, suggestive of a potential drug candidate
for COVID-19 (Yamamoto et al., 2004).
The most critical method for anti-SARS-CoV-2 drug discovery includes the
de novo development of new, specific drugs based upon the genomic and
biophysical understanding of this virus. For instance, the determination
of key SARS-CoV-2 targets may bring about the production of siRNA
molecules or inhibitors against specific viral enzymes correlated with
viral replication. Additionally, mAb targeting host receptors,
inhibitors of host cell proteases, host cell endocytosis viruses, along
with humanized mAb targeting the RBD, and antiviral peptides targeting
the S2 subunit offer various methodology and options for the design and
development of possible therapeutics. With the emerging outbreak of the
COVID-19 pandemic, the above-mentioned methods are critical for
identifying candidate drug composites that can be widely categorized
into virus-based and host-based therapy options.
Therapeutics options for SARS-CoV-2 in clinical
During the outbreak of the pandemic COVID-19, considerable efforts are
underway to discover novel therapeutic drugs for CoV infections. A wide
variety of agents has been selected as therapeutic options for
SARS-CoV-2 in clinical trials (Table 1).