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

Orf6 of SARS-CoV has been shown to play a role in antagonizing host interferon signaling 63 ; we identified a novel, high-confidence interaction between SARS-CoV-2 Orf6 and NUP98-RAE1, an interferon-inducible mRNA nuclear export complex 64 that is hijacked or degraded by multiple viruses, including VSV, Influenza-A, KSHV, and Polio, and is a restriction factor for Influenza-A infection 58,60,62, 65 . The X-ray structure of VSV M protein complexed with NUP98-RAE1 66 reveals key binding interactions that include a buried methionine residue on the M-protein packing into a hydrophobic pocket in RAE1, as well as neighboring acidic residues interacting with a basic patch on the NUP98-RAE1 complex (Fig 4b) . These binding features are also present in a conserved motif in the C-terminal region of SARS-CoV-2 Orf6 (Fig. 4b , Extended Data Fig. 8 ), providing a structural hypothesis for the observed SARS-CoV-2-NUP98-RAE1 interaction. Moreover, a peptide containing the binding region of the VSV M protein was previously shown to outcompete RNA binding to NUP98-RAE1, suggesting a role in interfering with mRNA export 66 . These observations suggest a viral strategy to target the RNA nuclear export activity of RAE1, potentially revealing a mode of interferon antagonism by SARS-CoV-2.