Broad-spectrum Antiviral Activity of eIF4a Inhibitors

MSK Internal Code SK2020-005

Broad-spectrum Antiviral Activity of eIF4a Inhibitors

MSK Internal Code SK2020-005

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SUMMARY OF INVENTION

Viruses depend on host proteins for several essential functions. For example, viral replication relies on the host translational machinery and is susceptible to inhibitors of translation.  Rocaglates, a class of natural compounds that include Silvestrol and its analogs, are potent inhibitors of translation.  CR-31B, one such Silvestrol analog, targets eIF4A, an RNA helicase and translation initiation factor.  Researchers from MSK and the University of Marburg have shown that CR-31B has potent broad-spectrum antiviral activity in primary cells and in an ex vivo bronchial epithelial cell system.  

The investigative team has demonstrated that CR-31B inhibits the replication of coronavirus, however, testing remains to be done against the specific strain causing the COVID-19 pandemic.  Additionally, CR-31B also inhibits replication of Zika virus, Lassa virus, and Crimean Congo hemorrhagic fever virus at low nanomolar concentrations and with low cytotoxicity in primary human cells.  

MSK researchers have extensively characterized CR-31B and other proprietary eIF4a inhibitors as anti-cancer agents.  These compounds are effective at low concentrations and show no overt toxicity in mice.  CR-31B could have a broad therapeutic window for the treatment of viral infections.  We are seeking partners to advance this class of compounds as antiviral therapeutic agents with an initial focus on coronavirus. 

ADVANTAGES

  • Broadly active against multiple RNA viruses
  • Difficult for virus to mutate and develop resistance since the drug target is not a viral protein
  • Broad therapeutic window—effective at low concentrations with low cytotoxicity in primary human cell.

MARKET OPPORTUNITY

There is a large unmet medical need for antiviral agents in general, especially with the ongoing COVID-19 pandemic for which there is no effective cure. 

PATENT INFORMATION

  • US Provisional application 62/980,943, pending, covering use of CR-31B as an antiviral agent

LEAD INVESTIGATOR

  • Hans-Guido Wendel, MD, Associate Member, Cancer Biology & Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering
  • Arnold Grünweller, PhD, Professor, Philipps University Marburg Germany

PUBLICATION

  • Christin Müller et al., (2019) Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (−) and the eIF4A-inhibitor Silvestrol. Antiviral Research (PubMed link)
  • Wolfe A.L. et al., (2014) RNA G-quadruplexes cause eIF4Adependent oncogene translation in cancer. Nature (PubMed link)

CONTACT INFORMATION

Kannan Krishnamurthy, PhD

Senior Manager, Business Development & Licensing
Tel: 646-888-1075
E-mail: krishnak@mskcc.org

Stage of Development

In vitro