Pharmacologic profiling reveals lapatinib as a novel antiviral against SARS-CoV-2 in vitro

Raymonda, Matthew H.; Ciesla, Jessica H.; Monaghan, Morgan; Leach, Justin; Asantewaa, Gloria; Smorodintsev-Schiller, Leonid A.; Lutz, Michael M.; Schafer, Xenia; Takimoto, Toru; Dewhurst, Stephen; Munger, Joshua; Harris, Isaac S.

doi:10.1016/j.virol.2021.11.008

Cited by 25 publications

(26 citation statements)

References 27 publications

(17 reference statements)

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“…With the emergence of highly pathogenic coronaviruses of zoonotic origin, especially the recent pandemic CoV2 that swept the globe causing high morbidity and mortality, the interest in coronavirus research increased. Due to its classification as level 2 pathogen, OC43 emerged as one of the model coronaviruses (59)(60)(61)(62)(63). In this study, we examined this viruses' ability to inhibit formation of SGs, one of the intrinsic host antiviral mechanisms, and compared it to that of the highly pathogenic CoV2.…”

Section: G3bp1 Overexpression Interferes With Oc43 Infectionmentioning

confidence: 99%

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

Dolliver

Kleer

Bui-Marinos

et al. 2022

Preprint

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Stress granules (SGs) are cytoplasmic condensates that often form as part of the cellular antiviral response. Despite the growing interest in understanding the interplay between SGs and other biological condensates and viral replication, the role of SG formation during coronavirus infection remains poorly understood. Several proteins from different coronaviruses have been shown to suppress SG formation upon overexpression, but there are only a handful of studies analyzing SG formation in coronavirus-infected cells. To better understand SG inhibition by coronaviruses, we analyzed SG formation during infection with the human common cold coronavirus OC43 (HCoV-OC43) and the highly pathogenic SARS-CoV2. We did not observe SG induction in infected cells and both viruses inhibited eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and SG formation induced by exogenous stress (e.g. sodium arsenite treatment). Furthermore, in SARS-CoV2 infected cells we observed a sharp decrease in the levels of SG-nucleating protein G3BP1. Ectopic overexpression of nucleocapsid (N) and non-structural protein 1 (Nsp1) from both HCoV-OC43 and SARS-CoV-2 inhibited SG formation. The Nsp1 proteins of both viruses inhibited arsenite-induced eIF2α phosphorylation, and the Nsp1 of SARS-CoV2 alone was sufficient to cause decrease in G3BP1 levels. This phenotype was dependent on the depletion of cytoplasmic mRNA mediated by Nsp1 and associated with nuclear retention of the SG-nucleating protein TIAR. To test the role of G3BP1 in coronavirus replication, we infected cells overexpressing EGFP-tagged G3BP1 with HCoV-OC43 and observed a significant decrease in infection compared to control cells expressing EGFP. The antiviral role of G3BP1 and the existence of multiple SG suppression mechanisms that are conserved between HCoV-OC43 and SARS-CoV2 suggest that SG formation may represent an important antiviral host defense that coronaviruses target to ensure efficient replication.

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Section: G3bp1 Overexpression Interferes With Oc43 Infectionmentioning

confidence: 99%

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

Dolliver

Kleer

Bui-Marinos

et al. 2022

Preprint

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“…VEROe6 cells (ATCC, #30-2003) were cultured in Minimum Essential Medium Eagle serum (MEM, Invitrogen) supplemented with 10% (v/v) fetal bovine serum (FBS), 1X GlutaMAX (Invitrogen #35050-061), and 1% penicillin-streptomycin at 37≥C in a 5% (v/v) CO2 atmosphere. HFFs were transduced with ACE2 (HFF-ACE2) with lentivirus as previously described 52 .…”

Section: Methodsmentioning

confidence: 99%

“…GFP expressing AD169, referred to as WT-GFP, was BADsubUL21.5 53 . OC43 and SARS-CoV-2, Isolate Hong Kong/VM20001061/2020 (BEI Resources NR-52282) were cultured as previously described 52 . All experiments involving live SARSCoV-2 were conducted in a biosafety level 3 facility at the University of Rochester.…”

Section: Methodsmentioning

confidence: 99%

“…All experiments involving live SARSCoV-2 were conducted in a biosafety level 3 facility at the University of Rochester. Viral stocks of HCMV, OC43 and SARS-CoV2 were propagated and titered as described previously 52 using a modified Reed & Muench TCID50 calculator from the Lindenbach lab 54 .…”

Section: Methodsmentioning

confidence: 99%

“…Analysis of RNA was carried out as previously described 52 . Briefly, RNA was extracted using Trizol (Invitrogen #15596026) and cDNA synthesis was completed using qScript cDNA Synthesis Kit (#95047-500).…”

Section: Methodsmentioning

confidence: 99%

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TNFα-induced metabolic reprogramming drives an intrinsic anti-viral state

Ciesla

Moreno

Munger

2022

Preprint

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Cytokines induce an anti-viral state, yet many of the functional determinants responsible for limiting viral infection are poorly understood. Here, we find that TNFα induces significant metabolic remodeling that is critical for its anti-viral activity. Our data demonstrate that TNFα activates glycolysis through the induction of muscle-specific hexokinase (HK2). Further, we show that glycolysis is broadly important for TNFα-mediated anti-viral defense, as its inhibition attenuates TNFα-mediated inhibition of evolutionarily divergent viruses. Stable-isotope tracing revealed that TNFα-mediated glycolytic activation promotes the biosynthesis of UDP-sugars (essential precursors of protein glycosylation) and that inhibition of glycolysis prevents the accumulation of several glycosylated anti-viral proteins. Consistent with the importance of glucose-driven glycosylation, glycosyl-transferase inhibition also attenuated the TNFα-induced anti-viral cell state. Collectively, our data indicate that cytokine-mediated metabolic remodeling is an essential component of the anti-viral response.

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Antiviral mechanisms of sorafenib against foot-and-mouth disease virus via c-RAF and AKT/PI3K pathways

Theerawatanasirikul,

Lueangaramkul,

Semkum

et al. 2023

Vet Res Commun

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Pharmacologic profiling reveals lapatinib as a novel antiviral against SARS-CoV-2 in vitro

Cited by 25 publications

References 27 publications

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

TNFα-induced metabolic reprogramming drives an intrinsic anti-viral state

Antiviral mechanisms of sorafenib against foot-and-mouth disease virus via c-RAF and AKT/PI3K pathways

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