Network-Based Identification and Pharmacological Targeting of Host Cell Master Regulators Induced by SARS-CoV-2 Infection

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, without 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.Funding Statement: This research was supported by the following NIH grants to A.C.: R35 CA197745 (Outstanding Investigator Award); U01 CA217858 (Cancer Target Discovery and Development); S10 OD012351 and S10 OD021764 (Shared Instrument Grants); by grants to S.B.: Deutsche Forschungsgemeinschaft (DFG) project numbers 415089553 (Heisenberg program), 240245660 (SFB1129), 278001972 (TRR186), and 272983813 (TRR179), and from the state of Baden Wuerttemberg (AZ: 33.7533.-6-21/5/1) and the Bundesministerium Bildung und Forschung (BMBF) (01KI20198A) and within the Network University Medicine - Organo-Strat COVID-19; by grants to M.L.S.: BMBF (01KI20239B) and DFG project 416072091; by grant to T.A.: ERC Consolidator grant METACELL (grant number 773089); by grant to M.K.J.: BCPM grant to Thomas Geiser (Department of Pulmonary Medicine, University Hospital/DBMR), and support from the Department of Urology of the Bern University Hospital; and to M.J.A.: research support from Karyopharm Therapeutics, Inc.Declaration of Interests: P.L. is Director of Single-Cell Systems Biology at DarwinHealth, Inc., a company that has licensed some of the algorithms used in this manuscript from Columbia University. G.B. is founder, CEO and equity holder of DarwinHealth, Inc. X.S. is Senior Computational Biologist at DarwinHealth, Inc. A.C. is founder, equity holder, and consultant of DarwinHealth Inc. M.J.A. is CSO and equity holder of DarwinHealth, Inc. Columbia University is also an equity holder in DarwinHealth Inc.Ethics Approval Statement: The protocol was approved by the “Ethics commission of the University Hospital Heidelberg” under the protocol S- 443/2017.