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

To identify small molecules targeting human proteins in the SARS-CoV-2 interactome, we sought ligands known to interact with the human proteins, often directly but also by pathway and complexes, drawing on chemoinformatics databases and analyses (Methods). Molecules were prioritized by the statistical significance of the interaction between the human and viral proteins; by their status as approved drugs, investigational new drugs (INDs, "clinical" in Table 1a ,b), or as preclinical candidates; by their apparent selectivity; and by their . CC-BY 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . availability (for purchase availability notes, see Supplemental Tables 3 and 4 ). Chemoinformatics searches yielded 15 approved drugs, four investigational new drugs (clinical), and 18 pre-clinical candidates (Table 1a) , while specialist knowledge revealed 12 approved drugs, 10 investigational new drugs (clinical), and 10 preclinical candidates (Table 1b) . Of the 332 human targets that interact with the viral bait proteins with high significance, 63 have drugs/INDs/preclinical molecules that modulate them (Fig. 3 ). If we reduce our protein interaction score threshold slightly, we find an additional four human targets, revealing a total of 67 human targets (Supplementary Tables 3 and 4 ). The drug-human protein associations may be overlaid on top of our protein interaction network, highlighting potentially druggable host interactions (Fig. 5a ).