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

There are several mechanistically interesting, and potentially disease-relevant drug-target interactions revealed in the chemoinformatic network (Fig. 5a) . Among them, the well-known chemical probe, Bafilomycin A1, is a potent inhibitor of the V1-ATPase, subunits of which interact with Nsp6 and M. Bafilomycin's inhibition of this cotransporter acts to prevent the acidification of the lysosome, inhibiting autophagy and endosome trafficking pathways, which may impact the viral life-cycle. Similarly, drugs exist to target several well-known epigenetic regulators prominent among the human interactors, including HDAC2, BRD2 and BRD4, which interact with viral proteins nsp5 and E, respectively (Figs. 3 and 5a). The approved drug Valproic acid (an anticonvulsant) and the pre-clinical candidate Apicidin inhibit HDAC2 with affinities of 62 μM and 120 nM, respectively. Clinical compounds ABBV-744 and CPI-0610 act on BRD2/4, with an affinity of 2 nM or 39 nM, respectively --several preclinical compounds also target bromodomain-containing proteins (Table 1a,b). As a final example, we were intrigued to observe that the SARS-CoV-2 Nsp6 protein interacts with the Sigma receptor, which is thought to regulate ER stress response 71 . Similarly, the Sigma2 receptor interacted with the vial protein orf9. Both Sigma1 and Sigma2 are promiscuous receptors that interact with many non-polar, cationic drugs. We prioritized several of these drugs based on potency or potential disease relevance, including the antipsychotic Haloperidol, which binds in the low nM range to both receptors 72 , and Chloroquine, which is currently in clinical trials for COVID-19 and has mid-nM activity vs the Sigma1 receptor, and low μM activity against the Sigma2 receptor. Because many patients are already treated with drugs that have off-target impact on Sigma receptors, associating clinical outcomes accompanying treatment with these drugs may merit investigation, a point to which we return. Finally, in addition to the druggable host factors, a few of which we have highlighted here, the SARS-CoV-2-human interactome reveals many traditionally "undruggable" targets. Among these, for instance, are components of the centriole such as CEP250, which interacts with the viral Nsp13. Intriguingly, a very recent patent disclosure revealed a natural product, WDB002, that directly and specifically targets CEP250. As a natural product, WDB002 would likely be harder to source than the molecules on which we have focused on here, but may well merit investigation. Similarly, other "undruggable" targets may be revealed to have compounds that could usefully perturb the viral-human interaction network, and act as leads to therapeutics.