Network-based identification and pharmacological targeting of host cell master regulators induced by SARS-CoV-2 infection

Laise, P.; Stanifer, M. L.; Bosker, G.; Sun, X.; Triana, S.; Doldan, P.; La Manna, F.; De Menna, M.; Realubit, R. B.; Pampou, S.; Karan, C.; Alexandrov, T.; Kruithof-de Julio, M.; Califano, A.; Boulant, S.; Alvarez, M. J.

doi:10.1101/2021.07.03.451001

bioRxiv · 10.1101/2021.07.03.451001

Network-based identification and pharmacological targeting of host cell master regulators induced by SARS-CoV-2 infection

Laise, P.·Stanifer, M. L.·Bosker, G.·Sun, X.·Triana, S.·Doldan, P.·La Manna, F.·De Menna, M.·Realubit, R. B.·Pampou, S.·Karan, C.·Alexandrov, T.·Kruithof-de Julio, M.·Califano, A.·Boulant, S.·Alvarez, M. J.

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Abstract

Precise characterization and targeting of host cell transcriptional machinery hijacked by SARS-CoV-2 remains challenging. To identify therapeutically targetable mechanisms that are critical for SARS-CoV-2 infection, here we elucidated the Master Regulator (MR) proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2. The analysis revealed coordinated inactivation of MR-proteins linked to regulatory programs potentiating efficiency of viral replication (detrimental host MR-signature) and activation of MR-proteins governing innate immune response programs (beneficial MR-signature). To identify MR-inverting compounds capable of rescuing activity of inactivated host MR-proteins, with-out adversely affecting the beneficial MR-signature, we developed the ViroTreat algorithm. Overall, >80% of drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 infection, without affecting cell viability. ViroTreat is fully generalizable and can be extended to identify drugs targeting the host cell-based MR signatures induced by virtually any pathogen.

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Laise, P., Stanifer, M. L., Bosker, G., Sun, X., Triana, S., Doldan, P., La Manna, F., De Menna, M., Realubit, R. B., Pampou, S., Karan, C., Alexandrov, T., Kruithof-de Julio, M., Califano, A., Boulant, S., Alvarez, M. J.. 2021-07-04. Network-based identification and pharmacological targeting of host cell master regulators induced by SARS-CoV-2 infection. https://doi.org/10.1101/2021.07.03.451001

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