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

More generally, this proteomic/chemoinformatic analysis is not only identifying drug and clinical molecules that might perturb the viral-human interactome, it gives these potentially therapeutic perturbations a mechanistic context. Among those that may be infection relevant are the inhibition of lysosomal acidification and trafficking with Bafilomycin A1, via inhibition of V-ATPase 74 , and modulation of the ER stress and the protein unfolding response pathway by targeting the Sigma1 and Sigma2 receptor by drugs like haloperidol (Fig. 5a , Tables 1a,b). Indeed, several of the human proteins in the interactome are targeted by drugs that have emerged phenotypically as candidate therapeutics for treating COVID-19, such as chloroquine 75, 76 . While we do not pretend to have identified the molecular basis of chloroquine's putative activity, we do note that this drug targets the Sigma1 and Sigma2 receptors at mid-nM and low μM concentrations, respectively. Similarly, antibiotics like azithromycin have also been mooted as treatments for COVID-19. While this too remains to be demonstrated, we note that Azithromycin has off-target activity against human mitochondrial ribosomes, components of which interact with the SARS-CoV-2 Nsp8 protein (MRPS5, MRPS27, MRPS2, and MRPS25). Other antibiotics that also have an off-target effect on mitochondrial ribosomes, such as chloramphenicol, tigecycline, and Linezolid 77,78 may also merit study for efficacy. Indeed, this logic may be extended. Many COVID-19 patients will be on the drugs identified here, treating pre-existing conditions. It may be useful to correlate clinical outcomes with the taking of these drugs, cross-referencing with the networks described here. In some senses, this is already occurring phenomenologically, leading to concerns about ACE inhibitors such as captopril and enalapril, and for NSAIDs. What this study provides is a systematic schema for clinical/drug associations going forward, giving them a mechanistic context that allows investigators to seek them directly.