A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV2 main protease

Baker, Jeremy D.; Uhrich, Rikki L; Kraemer, Gerald C.; Love, Jason E.; Kraemer, Brian C.

doi:10.1371/journal.pone.0245962

Cited by 49 publications

(35 citation statements)

References 44 publications

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“…The antiviral potency of RDV and telaprevir treatment alone against SARS-CoV-2 was approximately 99 nM and >10,000 nM, respectively ( Table 6 ). The low antiviral activity of telaprevir is consistent with published data ( 18 ). In the presence of telaprevir, a CatA inhibitor, RDV lost its antiviral potency in a dose-dependent manner, as demonstrated by rightward shifts in the virus replication titration curves ( Fig.…”

Section: Resultssupporting

confidence: 91%

Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells

Liclican

et al. 2021

Antimicrob Agents Chemother

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Remdesivir (RDV; GS-5734; Veklury®), the first FDA-approved antiviral to treat COVID-19, is a single diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV is taken up in the target cells and metabolized in multiple steps to form the active nucleoside triphosphate (TP) (GS-443902), which in turn acts as a potent and selective inhibitor of multiple viral RNA polymerases. In this report, we profiled the key enzymes involved in the RDV metabolic pathway with multiple parallel approaches: (1) bioinformatic analysis of nucleoside/tide metabolic enzyme mRNA expression using public human tissue and lung single-cell RNAseq datasets; (2) protein and mRNA quantification of enzymes in human lung tissue and primary lung cells; (3) biochemical studies on the catalytic rate of key enzymes; (4) effects of specific enzyme inhibitors on the GS-443902 formation; and (5) the effects of these inhibitors on RDV antiviral activity against SARS-CoV-2 in cell culture. Our data collectively demonstrated that carboxylesterase 1 (CES1) and cathepsin A (CatA) are enzymes involved in hydrolyzing RDV to its alanine intermediate Met X, which is further hydrolyzed to the monophosphate form by histidine triad nucleotide-binding protein 1 (HINT1). The monophosphate is then consecutively phosphorylated to diphosphate and triphosphate by cellular phosphotransferases. Our data support the hypothesis that the unique properties of RDV prodrug not only allow lung-specific accumulation critical for the treatment of respiratory viral infection such as COVID-19, they also enable efficient intracellular metabolism of RDV and its Met X to monophosphate and successive phosphorylation to form the active TP in disease-relevant cells.

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Section: Resultssupporting

confidence: 91%

Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells

Liclican

et al. 2021

Antimicrob Agents Chemother

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“…Targeting calpain proteases was shown to inhibit SARS-CoV-2 56 , SARS-CoV 57 and IAV replication 58 and to exert anti-inflammatory and tissue protective effects 59,60 including in a reovirus-induced myocarditis mouse model61. Beyond their host-targeted effects, Ac-Leu-Leu-Nle-CHO and aurothioglucose may have direct antiviral effects against the SARS-CoV-2 M pro or 3C-like proteases, respectively 56,62 . Lastly, josamycin is a natural macrolide antibiotic with an anti-inflammatory activity used in humans in Europe and Japan.…”

Section: Supplementary Discussionmentioning

confidence: 99%

Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects

Saul

Karim

Huang

et al. 2021

Preprint

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Effective therapies are needed to combat emerging viruses. Seventeen candidates that rescue cells from SARS-CoV-2-induced lethality and target diverse functions emerged in a screen of 4,413 compounds. Among the hits was lapatinib, an approved inhibitor of the ErbB family of receptor tyrosine kinases. Lapatinib and other pan-ErbB inhibitors suppress replication of SARS-CoV-2 and unrelated viruses with a high barrier to resistance. ErbB4, but not lapatinib's cancer targets ErbB1 and ErbB2, is required for SARS-CoV-2 entry and Venezuelan equine encephalitis virus infection and is a molecular target mediating lapatinib's antiviral effect. In human lung organoids, lapatinib protects from SARS-CoV-2-induced activation of pathways implicated in acute and chronic lung injury downstream of ErbBs (p38-MAPK, MEK/ERK, and AKT/mTOR), pro-inflammatory cytokine production, and epithelial barrier injury. These findings reveal regulation of viral infection, inflammation, and tissue injury via ErbBs and propose approved candidates to counteract these effects with implications for coronaviruses and unrelated viruses.

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“…But all viral encoded proteins are potential targets for inhibition of SARS-CoV-2 infection. Inhibitors of proteases are currently in the pipeline [107][108][109][110]. We hope that inhibitors targeting necessary protein-protein interactions beyond viral enzymes will be developed as well.…”

Section: Remarks and Perspectivesmentioning

confidence: 99%

SARS-CoV-2: from its discovery to genome structure, transcription, and replication

Tian²,

et al. 2021

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SARS-CoV-2 is an extremely contagious respiratory virus causing adult atypical pneumonia COVID-19 with severe acute respiratory syndrome (SARS). SARS-CoV-2 has a single-stranded, positive-sense RNA (+RNA) genome of ~ 29.9 kb and exhibits significant genetic shift from different isolates. After entering the susceptible cells expressing both ACE2 and TMPRSS2, the SARS-CoV-2 genome directly functions as an mRNA to translate two polyproteins from the ORF1a and ORF1b region, which are cleaved by two viral proteases into sixteen non-structural proteins (nsp1-16) to initiate viral genome replication and transcription. The SARS-CoV-2 genome also encodes four structural (S, E, M and N) and up to six accessory (3a, 6, 7a, 7b, 8, and 9b) proteins, but their translation requires newly synthesized individual subgenomic RNAs (sgRNA) in the infected cells. Synthesis of the full-length viral genomic RNA (gRNA) and sgRNAs are conducted inside double-membrane vesicles (DMVs) by the viral replication and transcription complex (RTC), which comprises nsp7, nsp8, nsp9, nsp12, nsp13 and a short RNA primer. To produce sgRNAs, RTC starts RNA synthesis from the highly structured gRNA 3' end and switches template at various transcription regulatory sequence (TRSB) sites along the gRNA body probably mediated by a long-distance RNA–RNA interaction. The TRS motif in the gRNA 5' leader (TRSL) is responsible for the RNA–RNA interaction with the TRSB upstream of each ORF and skipping of the viral genome in between them to produce individual sgRNAs. Abundance of individual sgRNAs and viral gRNA synthesized in the infected cells depend on the location and read-through efficiency of each TRSB. Although more studies are needed, the unprecedented COVID-19 pandemic has taught the world a painful lesson that is to invest and proactively prepare future emergence of other types of coronaviruses and any other possible biological horrors.

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A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV2 main protease

Cited by 49 publications

References 44 publications

Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells

Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells

Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects

SARS-CoV-2: from its discovery to genome structure, transcription, and replication

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