A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

David E. Gordon; Gwendolyn M. Jang; Mehdi Bouhaddou; Jiewei Xu; Kirsten Obernier; Matthew J O'Meara; Jeffrey Z. Guo; Danielle L. Swaney; Tia A. Tummino; Ruth Huttenhain; Robyn Kaake; Alicia L. Richards; Beril Tutuncuoglu; Helene Foussard; Jyoti Batra; Kelsey Haas; Maya Modak; Minkyu Kim; Paige Haas; Benjamin J. Polacco; Hannes Braberg; Jacqueline M. Fabius; Manon Eckhardt; Margaret Soucheray; Melanie Brewer; Merve Cakir; Michael J. McGregor; Qiongyu Li; Zun Zar Chi Naing; Yuan Zhou; Shiming Peng; Ilsa T. Kirby; James E. Melnyk; John S Chorba; Kevin Lou; Shizhong A. Dai; Wenqi Shen; Ying Shi; Ziyang Zhang; Inigo Barrio-Hernandez; Danish Memon; Claudia Hernandez-Armenta; Christopher J.P. Mathy; Tina Perica; Kala B. Pilla; Sai J. Ganesan; Daniel J. Saltzberg; Rakesh Ramachandran; Xi Liu; Sara B. Rosenthal; Lorenzo Calviello; Srivats Venkataramanan; Yizhu Lin; Stephanie A. Wankowicz; Markus Bohn; Phillip P. Sharp; Raphael Trenker; Janet M. Young; Devin A. Cavero; Joseph Hiatt; Theo Roth; Ujjwal Rathore; Advait Subramanian; Julia Noack; Mathieu Hubert; Ferdinand Roesch; Thomas Vallet; Björn Meyer; Kris M. White; Lisa Miorin; Oren S. Rosenberg; Kliment A. Verba; David Agard; Melanie Ott; Michael Emerman; Davide Ruggero; Adolfo Garcí-Sastre; Natalia Jura; Mark von Zastrow; Jack Taunton; Olivier Schwartz; Marco Vignuzzi; Christophe d'Enfert; Shaeri Mukherjee; Matt Jacobson; Harmit S. Malik; Danica G Fujimori; Trey Ideker; Charles S Craik; Stephen Floor; James S. Fraser; John Gross; Andrej Sali; Tanja Kortemme; Pedro Beltrao; Kevan Shokat; Brian K. Shoichet; Nevan J. Krogan

We identified a number of cellular proteins implicated in innate immune signaling that are targeted by several SARS-CoV-2 viral proteins. Interestingly, we found that Nsp13 interacts with two key players of IFN signaling pathway including TANK-binding kinase 1 (TBK1) and TANK-binding kinase 1-binding protein 1 (TBKBP1/SINTBAD). SINTBAD acts as a critical adaptor protein between TBK1 and IKKi and therefore mediates induction of IRF-dependent transcription 41 . Further, Nsp13 interacts with multiple proteins of the TLE family, which are known to modulate NF-κB inflammatory response 42-44 . RNF41/Nrdp1, an E3 ubiquitin ligase is targeted by Nsp15 protein which promotes activation of TBK1 and IRF3 and therefore increases type I interferon production 45 . Two other E3 ubiquitin ligases, TRIM59 and MIB1 regulate antiviral innate immune signaling and are usurped by Orf3a and Nsp9, respectively 46,47 . Orf9c protein was found to interact with multiple proteins that modulate IkB kinase and NF-kB signaling pathway including NLRX1, F2RL1, NDFIP2 48-50 . We also found that Orf9b interacts with a mitochondrial import receptor, Tom70, which acts as an essential adaptor linking MAVS to TBK1/IRF3, resulting in the activation of IRF-3 51 .