A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV-2 main protease

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

doi:10.1101/2020.07.10.197889

Cited by 8 publications

(8 citation statements)

References 43 publications

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“…Aurothioglucose has been previously used for the treatment of rheumatoid arthritis and was thought to inhibit the activity of adenylyl cyclase in pro-inflammatory pathways (Botz et al, 2014). While it recently emerged as a potential inhibitor of the SARS-CoV-2 3C-like protease, since the IC50 was 13.32 μM, this is unlikely to be the mechanism of antiviral action (Baker et al, 2021). Ac-Leu-Leu-Nle-CHO is a competitive inhibitor of the neutral, calcium-dependent cysteine proteases calpain 1 and 2 (CAPN1 and 2) used as a research tool.…”

Section: 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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Section: 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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“…Interestingly, several caspase inhibitors were shown to target the main protease of SARS-CoV-2 M pro , including pan-caspase inhibition with Z-VAD(OMe)-FMK and discriminate inhibitors Z-DEVD-FMK and Z-IETD-FMK, for caspase-3 and caspase-8, respectively ( 110 ). Furthermore, among ~6,070 drugs screened, EMR was identified to inhibit the activity of Mpro in vitro and through computation screening shown to bind to ACE2 ( 111 , 112 ). Nonetheless, while several targeted and indiscriminate caspase inhibitors have been identified and developed with intended therapeutic use, only few have advanced into clinical trials, and none are used clinically.…”

Section: Therapeutic Potential Of Targeting Caspase Pathways For Covi...mentioning

confidence: 99%

Emerging Insights on Caspases in COVID-19 Pathogenesis, Sequelae, and Directed Therapies

et al. 2022

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Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant global health emergency with new variants in some cases evading current therapies and approved vaccines. COVID-19 presents with a broad spectrum of acute and long-term manifestations. Severe COVID-19 is characterized by dysregulated cytokine release profile, dysfunctional immune responses, and hypercoagulation with a high risk of progression to multi-organ failure and death. Unraveling the fundamental immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and design of more effective therapeutic interventions for individuals at the highest risk of severe outcomes. Caspases are expressed in both immune and non-immune cells and mediate inflammation and cell death, including apoptosis and pyroptosis. Here we review accumulating evidence defining the importance of the expression and activity of caspase family members following SARS-CoV-2 infection and disease. Research suggests SARS-CoV-2 infection is linked to the function of multiple caspases, both mechanistically in vitro as well as in observational studies of individuals with severe COVID-19, which may further the impact on disease severity. We also highlight immunological mechanisms that occur in severe COVID-19 pathology upstream and downstream of activated caspase pathways, including innate recognition receptor signaling, inflammasomes, and other multiprotein complex assembly, inflammatory mediators IL-1β and IL-18, and apoptotic and pyroptotic cell death. Finally, we illuminate discriminate and indiscriminate caspase inhibitors that have been identified for clinical use that could emerge as potential therapeutic interventions that may benefit clinical efforts to prevent or ameliorate severe COVID-19.

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“…The pan-caspase inhibitor, EMR has been shown in a bioinformatics computational screen to binding to the COVID-19 receptor ACE2, suggesting the potential to block cell entry (71). In a separate unrelated study, a screen of ~6,070 drugs with a known 28 previous history of use in humans was conducted to identify compounds that inhibit the activity of SARS-CoV-2 main protease Mpro in vitro (72). EMR was shown to be among 50 compounds with activity against Mpro with an overall hit rate <0.75%.…”

Section: Discussionmentioning

confidence: 99%

Caspases in COVID-19 Disease and Sequela and the Therapeutic Potential of Caspase Inhibitors

Plassmeyer¹,

Alpan²,

Corley

et al. 2020

Preprint

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At present, there are is no effective vaccine and only one FDA approved early-stage therapy against infection with the SARS-CoV-2 virus to prevent disease progression. The excessive inflammation and tissue damage associated with COVID-19 can lead to immediate (i.e. respiratory failure, sepsis, and ultimately, death) or long-term health problems (i.e. fatigue, dyspnea, cough, joint pain, anosmia) and the risk for these complications are higher in the elderly population, certain ethnic groups, as well as those with various co-morbid conditions. Cellular caspases play a role in the pathophysiology of a number of disorders that overlap with the list of co-morbid conditions seen in severe COVID-19. In this study, we assessed transcriptional states of caspases in immune cells from COVID-19 patients and profiled intra-cellular caspases in immune cells and red blood cells derived from a spectrum of COVID-19 patients hospitalized with acute disease or convalescent. Gene expression levels of select caspases were increased in in vitro SARS-CoV-2 infection models and single cell RNA-Seq data of peripheral blood from COVID-19 patients showed a distinct pattern of caspase expression in T cell, neutrophils, and dendritic cells. Flow cytometric evaluation of CD4 T cells showed up-regulation of caspase-1 in hospitalized COVID-19 patients compared to unexposed controls, with the exception of a subset of patients with asthma and chronic rhinosinusitis (CRS). Convalescent COVID-19 patients with lingering symptoms (long haulers) showed persistent up-regulation of caspase-1 in CD4 T cells that was attenuated ex vivo following co-culture with a select pan-caspase inhibitor. Further, we observed elevated caspase 3 levels in red blood cells from COVID-19 patients compared to controls that were responsive to caspase inhibition. Taken together, our results expose an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate, reduce, or prevent severe COVID-19 outcomes.

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A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV-2 main protease

Cited by 8 publications

References 43 publications

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

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

Emerging Insights on Caspases in COVID-19 Pathogenesis, Sequelae, and Directed Therapies

Caspases in COVID-19 Disease and Sequela and the Therapeutic Potential of Caspase Inhibitors

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