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

Laise, Pasquale; Stanifer, Megan L.; Bosker, Gideon; Sun, Xiaoyun; Triana, Sergio; Doldan, Patricio; Manna, Federico La; De Menna, Marta; Realubit, Ronald B.; Pampou, Sergey; Karan, Charles; Alexandrov, Theodore; Kruithof-de Julio, Marianna; Califano, Andrea; Boulant, Steeve; Alvarez, Mariano J.

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.