Following its infection, SARS-CoV-2 utilizes cellular networks to enable its efficient replication. Key for its success in hijacking cellular systems of host cells lies in the takeover of the translational apparatus, whereby the virus requires eukaryotic translation initiation complex 4F (eIF4F) activity. To this end, cap-dependent and eIF4F- driven viral genome RNA translation is essential for production of the viral proteins required for its replication. Notably, cancer cells rewire their RNA translational machinery, as often reflected by enhanced activity and/or expression of eIF4F subunits leading to increased complex activity. Thus, SARS-CoV-2 and translational perturbations in cancer may converge on cap-dependent translation and, in particular, on the eIF4F complex. Accordingly, a different degree of susceptibility to SARS-CoV-2 infection is expected in cancer cells based on their pre-rewiring of the RNA translation machinery. The underlying hypothesis of this proposal is that targeting components of the eIF4F complex is expected to provide novel therapeutic modality for inhibition of SARS-CoV-2 replication, while exerting anti-neoplastic effects across broad spectrum of cancers. To test this, we will define the effectiveness of RNA translation modulators, we have developed, in attenuating SARS- CoV-2 effect on eIF4F activity in lung cancer cells susceptible to coronavirus infection. The effect of RNA translation modulators on SARS-CoV-2 infected lung cancer cells response to commonly used therapy will be also assessed. This is anticipated to improve understanding of coronavirus biology in context of neoplasia and in long-term provide therapeutic modalities for cancer patients infected with SARS-CoV-2 or other coronaviruses anticipated to cause future pandemics.
This supplemental application for SARS-COV-2 study will test the hypothesis that targeting components of the eIF4F complex offers novel therapeutic modality for inhibition of SARS-CoV-2 replication, while exerting anti- neoplastic effects across broad spectrum of cancers.
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