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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.
4.2.1. Bemcentinib
Bemcentinib (BGB324/R-428), a first-in-class highly selective oral AXL tyrosine kinase inhibitor in phase II development, was also predicted to stably occupy the nsp16/nsp10 activating interface. Although mainly recognized for its ability to block epithelial–mesenchymal transition phenomena in various cancer types [93,94,95], bemcentinib is now known for its anti-inflammatory and anti-fibrotic roles in non-cancer diseases [96,97], which are two phenotypic aspects that might be relevant in the therapeutic management of COVID-19. Moreover, AXL is a family member of the TAM receptor tyrosine kinases that operates both as a pleiotropic inhibitor of the innate immune response and a docking site during the cellular entry of some viruses [98,99,100]. As AXL receptor signaling participates in the downmodulation of interferon-related host immune responses to promote viral infection, inhibiting AXL function might be a new therapeutic avenue toward reducing the transmission of some of the most troublesome emerging enveloped viruses, including dengue, West Nile, Ebola, lentivirus, and most recently, Zika [99,100]. If experimentally confirmed as a blocker of the nsp16/nsp10-driven viral innate immunoevasion via suppression of viral RNA 2′-O-methylation, bemcentinib might also stimulate an advantageous increase in the early expression of interferon-stimulated genes that are capable of promoting a greater attenuation of SARS-CoV-2 replication. Bemcentinib was recently shown to block lysosomal acidification and promote the accumulation of autophagosomes in cancer cells independently of its inhibitory effects on AXL [101,102], thereby suggesting an additional overlapping mechanism with the above-mentioned lysosomotropic agents.
5. Conclusions
The COVID-19-causing virus SARS-CoV-2 has evolved distinct 2′-O’-MTase machinery to autonomously modify the 5′ cap of its RNA. Such 2′-O-methylation is a crucial mechanism used to subvert innate host antiviral responses by escaping interferon-stimulated proteins that are capable of detecting non-2′-O-methylated viral RNA and inhibiting its translation [40]. Although the previous biochemical and structural delineation of distinctive activating traits of nsp16 by nsp10 immediately suggested a new way to design and develop highly SARS-CoV-2-specific antivirals [45,46], very few attempts have been made to reactivate the innate immune restriction and antagonism of SARS-CoV-2 RNAs by pharmacologically preventing their RNA cap 2′-O-methylation. Here, we aimed to systematically identify repurposable drugs that we predict can target the RNA cap 2′-O-MTase nsp16/nsp10 protein complex but also other molecular and clinical traits specific to SARS-CoV-2 and COVID-19. Although we acknowledge that our final computational prediction might appear too wide for pre-clinical and clinical validation, we expect that by providing a multi-layer network framework (Figure 6), our findings should help to select the narrowest list of candidates that can be rapidly tested before evaluating their in vivo efficiency and side-effects. Indeed, some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, and phthalocyanine) might be suitable for rapid repurposing to pharmacologically reactivate the innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2′-O-methylation.
Link: https://www.mdpi.com/1999-4915/12/5/525/htm#B98-viruses-12-00525
Vi får sjå. Tenker ihvertfall at dette er en av de få sjansene man har på børsen til å kunne få 3-5x på veldig kort tid (1.-30. juni en gang) om alt klaffer. Så jeg vil ikke la den sjansen gå fra meg ihvertfall, men opp til hver enkelt hva man gjør. Nedsiden ser ikke spesielt skummel ut da det er masse penger på bok og fortsatt selskapets pipeline fult finansiert i en god periode framover.
