1. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
- Author
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Gordon, David E, Jang, Gwendolyn M, Bouhaddou, Mehdi, Xu, Jiewei, Obernier, Kirsten, White, Kris M, O'Meara, Matthew J, Rezelj, Veronica V, Guo, Jeffrey Z, Swaney, Danielle L, Tummino, Tia A, Hüttenhain, Ruth, Kaake, Robyn M, Richards, Alicia L, Tutuncuoglu, Beril, Foussard, Helene, Batra, Jyoti, Haas, Kelsey, Modak, Maya, Kim, Minkyu, Haas, Paige, Polacco, Benjamin J, Braberg, Hannes, Fabius, Jacqueline M, Eckhardt, Manon, Soucheray, Margaret, Bennett, Melanie J, Cakir, Merve, McGregor, Michael J, Li, Qiongyu, Meyer, Bjoern, Roesch, Ferdinand, Vallet, Thomas, Mac Kain, Alice, Miorin, Lisa, Moreno, Elena, Naing, Zun Zar Chi, Zhou, Yuan, Peng, Shiming, Shi, Ying, Zhang, Ziyang, Shen, Wenqi, Kirby, Ilsa T, Melnyk, James E, Chorba, John S, Lou, Kevin, Dai, Shizhong A, Barrio-Hernandez, Inigo, Memon, Danish, Hernandez-Armenta, Claudia, Lyu, Jiankun, Mathy, Christopher JP, Perica, Tina, Pilla, Kala Bharath, Ganesan, Sai J, Saltzberg, Daniel J, Rakesh, Ramachandran, Liu, Xi, Rosenthal, Sara B, Calviello, Lorenzo, Venkataramanan, Srivats, Liboy-Lugo, Jose, Lin, Yizhu, Huang, Xi-Ping, Liu, YongFeng, Wankowicz, Stephanie A, Bohn, Markus, Safari, Maliheh, Ugur, Fatima S, Koh, Cassandra, Savar, Nastaran Sadat, Tran, Quang Dinh, Shengjuler, Djoshkun, Fletcher, Sabrina J, O'Neal, Michael C, Cai, Yiming, Chang, Jason CJ, Broadhurst, David J, Klippsten, Saker, Sharp, Phillip P, Wenzell, Nicole A, Kuzuoglu-Ozturk, Duygu, Wang, Hao-Yuan, Trenker, Raphael, Young, Janet M, Cavero, Devin A, Hiatt, Joseph, Roth, Theodore L, Rathore, Ujjwal, Subramanian, Advait, Noack, Julia, Hubert, Mathieu, Stroud, Robert M, Frankel, Alan D, Rosenberg, Oren S, Verba, Kliment A, Agard, David A, Ott, Melanie, Emerman, Michael, and Jura, Natalia
- Subjects
General Science & Technology ,viruses ,sigma ,Antiviral Agents ,Mass Spectrometry ,Vaccine Related ,Viral Proteins ,Betacoronavirus ,Rare Diseases ,Protein Domains ,Biodefense ,Receptors ,Protein Interaction Mapping ,Chlorocebus aethiops ,Animals ,Humans ,Innate ,Viral ,Molecular Targeted Therapy ,Protein Interaction Maps ,Vero Cells ,Pandemics ,Lung ,SKP Cullin F-Box Protein Ligases ,SARS-CoV-2 ,Prevention ,Immunity ,Drug Repositioning ,Molecular ,COVID-19 ,Pneumonia ,Preclinical ,COVID-19 Drug Treatment ,HEK293 Cells ,Emerging Infectious Diseases ,Orphan Drug ,Infectious Diseases ,Good Health and Well Being ,5.1 Pharmaceuticals ,Protein Biosynthesis ,Host-Pathogen Interactions ,Pneumonia & Influenza ,Drug Evaluation ,Immunization ,Development of treatments and therapeutic interventions ,Coronavirus Infections ,Infection ,Cloning ,Protein Binding - Abstract
A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease2019 (COVID-19), has infected over 2.3million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66druggable human proteins or host factors targeted by 69compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
- Published
- 2020