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. These drugs possess the distinct preponderance of easy access to known pharmacokinetic and pharmacodynamic features, dose regimens, and adverse effects. 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. 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). 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. 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. 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.

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.

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