The rocaglate CR-31-B (−) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrations in vitro and ex vivo

Müller, Christin; Obermann, Wiebke; Karl, Nadja; Wendel, Hans Guido; Taroncher-Oldenburg, Gaspar; Pleschka, Stephan; Hartmann, Roland K.; Grünweller, Arnold; Ziebuhr, John

doi:10.1016/j.antiviral.2021.105012

Cited by 31 publications

(83 citation statements)

References 42 publications

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“…With a significant increase in EIF4A1 in platelets of COVID-19 patients, we identified another protein that may be directly related to viral RNA translation ( 50 , 51 ). The association of mortality with EIF4A1 was similar to that of TALDO1, with a significant decrease (FC = 0.74; p = 0.009) in survivors between days 0 and days 4–5.…”

Section: Resultsmentioning

confidence: 97%

“…The helicase EIF4A is part of the cellular EIF4F translation initiation complex which is required for mRNA binding to the ribosome. In line, inhibitors of this factor such as Zotatifin and Rocaglate inhibit the EIF4A-dependent mRNA translation initiation, which leads to greatly reduced viral RNA translation in infected cells, including SARS-CoV-2 ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

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Platelet Phenotype Analysis of COVID-19 Patients Reveals Progressive Changes in the Activation of Integrin αIIbβ3, F13A1, the SARS-CoV-2 Target EIF4A1 and Annexin A5

Ercan

Schrottmaier

Pirabe

et al. 2021

Front. Cardiovasc. Med.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Platelet Phenotype Analysis of COVID-19 Patients Reveals Progressive Changes in the Activation of Integrin αIIbβ3, F13A1, the SARS-CoV-2 Target EIF4A1 and Annexin A5

Ercan

Schrottmaier

Pirabe

et al. 2021

Front. Cardiovasc. Med.

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“…Furthermore, in peripheral blood mononuclear cells (PBMCs) silvestrol inhibits the expression of MERS-CoV structural and nonstructural proteins (N, nsp8) and the formation of viral replication/transcription complexes [ 166 ]. Additional reports showed that a synthetic rocaglate CR-31-B (-) possesses antiviral activity against HCoV-229E, similar to silvesterol, and SARS-CoV-2 replication in both in vitro and ex vivo studies [ 167 , 168 ]. Since, to date, chemical synthesis of silvestrol remains difficult, alternative synthetic rocaglate such as the CR-31-B (-) are desirable and promising anti-coronaviruses agents.…”

Section: Natural Compounds Against Emerging and Re-emerging Virusesmentioning

confidence: 99%

Antiviral Activity Exerted by Natural Products against Human Viruses

Musarra‐Pizzo

Pennisi

Ben-Amor

et al. 2021

Viruses

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Viral infections are responsible for several chronic and acute diseases in both humans and animals. Despite the incredible progress in human medicine, several viral diseases, such as acquired immunodeficiency syndrome, respiratory syndromes, and hepatitis, are still associated with high morbidity and mortality rates in humans. Natural products from plants or other organisms are a rich source of structurally novel chemical compounds including antivirals. Indeed, in traditional medicine, many pathological conditions have been treated using plant-derived medicines. Thus, the identification of novel alternative antiviral agents is of critical importance. In this review, we summarize novel phytochemicals with antiviral activity against human viruses and their potential application in treating or preventing viral disease.

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“…For example, dose-dependent inhibition by silvestrol and CR-31-B (-) was shown for human coronavirus 229E (HCoV-229E), MERS-CoV and SARS-CoV-2 replication in vitro, with EC50 values in the range of 1-3 nM [81]. In an ex vivo bronchial epithelial cell system, HCoV-229E and SARS-CoV-2 replication was reduced to undetectable levels in the presence of 100 nM CR-31-B (-) [82]. A comprehensive analysis of the SARS-CoV-2 protein interaction map published in early 2020 identified the host translational machinery, and in particular eEF1A and eIF4A, as top targets for drug repurposing aimed at abolishing SARS-CoV-2 replication [83].…”

Section: Positive (+)-Stranded Rna Viruses 421 Coronaviridaementioning

confidence: 99%

Targeting the DEAD-box RNA Helicase eIF4A with Rocaglates - A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics

Taroncher-Oldenburg¹,

Müller

Obermann

et al. 2021

Preprint

Self Cite

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The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the host’s protein synthesis machinery for replication. Several natural compounds that target the cellular DEAD-box RNA helicase eIF4A, a key component of the eukaryotic translation initiation complex eIF4F, have emerged as potential broad-spectrum antivirals. Rocaglates, a group of flavaglines of plant origin that clamp mRNAs with highly structured 5’UTRs onto the surface of eIF4A through specific stacking interactions, exhibit the largest selectivity and potential therapeutic indices among all known eIF4A inhibitors. Their unique mechanism of action limits the inhibitory effect of rocaglates to the translation of eIF4A-dependent viral mRNAs and a minor fraction of host mRNAs exhibiting stable RNA secondary structures and/or polypurine sequence stretches in their 5´UTRs, resulting in minimal potential toxic side effects. Maintaining a favorable safety profile while inducing efficient inhibition of a broad-spectrum of RNA viruses makes rocaglates into primary candidates for further development as pan-antiviral therapeutics.

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The rocaglate CR-31-B (−) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrations in vitro and ex vivo

Cited by 31 publications

References 42 publications

Platelet Phenotype Analysis of COVID-19 Patients Reveals Progressive Changes in the Activation of Integrin αIIbβ3, F13A1, the SARS-CoV-2 Target EIF4A1 and Annexin A5

Platelet Phenotype Analysis of COVID-19 Patients Reveals Progressive Changes in the Activation of Integrin αIIbβ3, F13A1, the SARS-CoV-2 Target EIF4A1 and Annexin A5

Antiviral Activity Exerted by Natural Products against Human Viruses

Targeting the DEAD-box RNA Helicase eIF4A with Rocaglates - A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics

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