Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2′-O-methyltransferase (2′-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2′-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2′-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique “activating surface” between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed ≈9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10–drug complexes, we considered their pharmacological overlapping with functional modules of the virus–host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2′-O-methylation.
Highlights
As of 4 May 2020, the pandemic of coronavirus disease 2019 (COVID-19) respiratory disease caused by the pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to more than 3,500,000 confirmed cases and more than 250,000 deaths worldwide [1,2,3,4,5]
Clinical trials evaluating the survival or time to clinical improvement in severely ill adult patients hospitalized for COVID-19 after adding remdesivir or hydroxychloroquine to standard supportive care, and clinical trials exploring hydroxychloroquine for preventing secondary SARS-CoV-2 transmission following initial contact exposure, are either recruiting or underway
Human coronavirus which provides the viral mRNA the ability to camouflage itself from the host cell [64]
Summary
As of 4 May 2020, the pandemic of coronavirus disease 2019 (COVID-19) respiratory disease caused by the pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to more than 3,500,000 confirmed cases and more than 250,000 deaths worldwide [1,2,3,4,5].Laboratory-based studies using the nucleotide analog remdesivir—a pan-inhibitor of viralRNA-dependent RNA polymerases—and preliminary clinical reports with (hydroxy)chloroquine—an approved, anti-inflammatory drug used to treat malaria, lupus, and rheumatoid arthritis—suggest their potential benefit against SARS-CoV-2 infection and the possible amelioration of viral shedding [6,7,8,9,10,11,12,13].clinical trials evaluating the survival or time to clinical improvement in severely ill adult patients hospitalized for COVID-19 after adding remdesivir or hydroxychloroquine to standard supportive care, and clinical trials exploring hydroxychloroquine for preventing secondary SARS-CoV-2 transmission following initial contact exposure, are either recruiting or underway. The current development of novel therapeutics to counteract SARS-CoV-2 infection can be categorized into at least four different strategies, namely: (a) broad-spectrum anti-virals (e.g., remdesivir, ribavirin, cyclophilin, and interferon) [14,15]; (b) drugs targeting the proinflammatory hypercytokinemia (termed “cytokine storm”) driving the transition from first COVID-19 symptoms to acute respiratory distress syndrome (e.g., IL-6 antibody blockers, IL-1 receptor antagonists, and JAK inhibitors) [16,17,18,19,20]; (c) inhibitors of host cell proteases that participate in the priming of the viral Spike (S) glycoprotein [21,22,23,24]; and (d) therapeutics targeting the host–virus interface linking the viral S protein to the angiotensin-converting enzyme 2 (ACE2) receptor in host cells [25,26,27,28,29,30,31,32,33]. The bulk of the drug repurposing efforts seem to be directed toward pharmacologically targeting 3CLpro/nsp5-dependent viral replication [36,37], RdRp/nsp12-driven viral RNA synthesis, and S protein-driven viral cellular entry [22]
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