S-adenosylmethionine-dependent methyltransferase inhibitor DZNep blocks transcription and translation of SARS-CoV-2 genome with a low tendency to select for drug-resistant viral variants

Kumar, Ram; Khandelwal, Nitin; Chander, Yogesh; Nagori, Himanshu; Verma, Ashu; Barua, Aditya; Godara, Bhagraj; Pal, Yash; Gulati, Baldev R.; Tripathi, Bhupendra Nath; Barua, Sanjay; Kumar, Naveen

doi:10.1016/j.antiviral.2021.105232

Cited by 26 publications

(19 citation statements)

References 67 publications

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“…DZNep was also shown to impair viral mRNA cap methylation in the context of vesicular stomatitis virus infection and reduce viral mRNA translation (Gibbons et al , 2021 ). Recently, DZNep was reported to be antiviral against SARS‐CoV‐2 in vitro and in ovo (Kumar et al , 2022 ), leading to viral RNA m6A methylation and cap maturation defects and consequently to reduced viral protein production and inhibition of virus replication (Kumar et al , 2022 ). Overall, the above‐mentioned independent work offers further evidence and supports findings presented herein toward demonstrating the treatment potential of SCIs against COVID‐19.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of SARS‐CoV‐2 replication and associated inflammation by concomitant targeting of viral and host cap 2'‐O‐ribose methyltransferases

et al. 2022

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The SARS‐CoV‐2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'‐O‐ribose cap needed for viral immune escape. We find that the host cap 2'‐O‐ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS‐CoV‐2 replication. Using in silico target‐based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti‐SARS‐CoV‐2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co‐substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro , in ex vivo , and in a mouse infection model and synergizes with existing COVID‐19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection‐induced hyperinflammation and reduces lung fibrosis markers ex vivo . Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID‐19.

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Section: Discussionmentioning

confidence: 99%

Attenuation of SARS‐CoV‐2 replication and associated inflammation by concomitant targeting of viral and host cap 2'‐O‐ribose methyltransferases

et al. 2022

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“…An examination of m 6 A modification kinetics in African green monkey kidney epithelial (Vero) cells [807] infected by SARS-CoV-2 discovered distinct peaks during the first 12 h of infection where m 6 A modified SARS-CoV-2 RNA peaked at 10 hpi-12 hpi (~100%+), whereas the relative level of m 6 A modification was significantly higher at 2 hpi (~10%) compared to 4 hpi (~5%) and 6 hpi (4%) [808]. The use of different cell types and the time of extraction post-infection may also conceivably affect the results obtained from infected cells to account for contradictory observations reported in literature.…”

Section: Is M 6 a A Positive Or Negative Regulator Of Sars-cov-2 Repl...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

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“…HnRNP A2/B1 is crucial to oligodendrocyte and neural mRNA trafficking (44). Some coronaviruses were reported to be associated with hnRNP A1 (45)(46)(47)(48)(49)(50)(51). An early study suggested that the nucleocapsid protein (N protein) of SARS coronavirus had a high affinity with hnRNP A1, and the protein-protein interaction requires 161-220 aa of SARS coronavirus N protein and 203-320 aa of hnRNP A1 (45).…”

Section: Roles Of Heterogeneous Nuclear Ribonucleoproteins In the Pos...mentioning

confidence: 99%

“…It was also suggested that hnRNP A1 might participate in the switch from viral translation to replication because N6-methyl adenosine (m6A) marked SARS-CoV-2 RNA recruit hnRNP A1 and enhance viral genome transcription while suppressing translation. And this interaction could be inhibited by 3-Deazaneplanocin A (DZNep) (46). And During SARS-CoV-2 infection, the cellular location of hnRNP A2/B1 is rearranged by NSP1, leading to restrained immune response and enhancing infection by SARS-CoV-2 and b-coronavirus, but the mechanism by which this occurs remains to be explained (36).…”

Section: Roles Of Heterogeneous Nuclear Ribonucleoproteins In the Pos...mentioning

confidence: 99%

Multiple functions of heterogeneous nuclear ribonucleoproteins in the positive single-stranded RNA virus life cycle

et al. 2022

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The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RNA binding proteins that are implicated in RNA metabolism, such as alternative splicing, mRNA stabilization and translational regulation. According to their different cellular localization, hnRNPs display multiple functions. Most hnRNPs were predominantly located in the nucleus, but some of them could redistribute to the cytoplasm during virus infection. HnRNPs consist of different domains and motifs that enable these proteins to recognize predetermined nucleotide sequences. In the virus-host interactions, hnRNPs specifically bind to viral RNA or proteins. And some of the viral protein-hnRNP interactions require the viral RNA or other host factors as the intermediate. Through various mechanisms, hnRNPs could regulate viral translation, viral genome replication, the switch of translation to replication and virion release. This review highlights the common features and the distinguish roles of hnRNPs in the life cycle of positive single-stranded RNA viruses.

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S-adenosylmethionine-dependent methyltransferase inhibitor DZNep blocks transcription and translation of SARS-CoV-2 genome with a low tendency to select for drug-resistant viral variants

Cited by 26 publications

References 67 publications

Attenuation of SARS‐CoV‐2 replication and associated inflammation by concomitant targeting of viral and host cap 2'‐O‐ribose methyltransferases

Attenuation of SARS‐CoV‐2 replication and associated inflammation by concomitant targeting of viral and host cap 2'‐O‐ribose methyltransferases

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Multiple functions of heterogeneous nuclear ribonucleoproteins in the positive single-stranded RNA virus life cycle

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