A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disr...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Nature (London) Jg. 583; H. 7816; S. 459 - 468
Hauptverfasser:	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 J P, 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 C J, 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, Jura, Natalia
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	England 16.07.2020
Schlagworte:	Animals Antiviral Agents - classification Antiviral Agents - pharmacology Betacoronavirus - drug effects Betacoronavirus - genetics Betacoronavirus - metabolism Betacoronavirus - pathogenicity Chlorocebus aethiops Cloning, Molecular Coronavirus Infections - drug therapy Coronavirus Infections - immunology Coronavirus Infections - metabolism Coronavirus Infections - virology COVID-19 COVID-19 Drug Treatment Drug Evaluation, Preclinical Drug Repositioning HEK293 Cells Host-Pathogen Interactions - drug effects Humans Immunity, Innate Mass Spectrometry Molecular Targeted Therapy Pandemics Pneumonia, Viral - drug therapy Pneumonia, Viral - immunology Pneumonia, Viral - metabolism Pneumonia, Viral - virology Protein Binding Protein Biosynthesis - drug effects Protein Domains Protein Interaction Mapping Protein Interaction Maps Receptors, sigma - metabolism SARS-CoV-2 SKP Cullin F-Box Protein Ligases - metabolism Vero Cells Viral Proteins - genetics Viral Proteins - metabolism
ISSN:	0028-0836, 1476-4687
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption . 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 66 druggable human proteins or host factors targeted by 69 compounds (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.
Bibliographie:	AUTHOR CONTRIBUTIONS Study conception by NJK, DEG. Genome annotation by DEG, GMJ, and BJP. Molecular cloning by DEG, GMJ, JZG. Cell culture, affinity purifications and peptide digestion by GMJ and JX. Mass spectrometer operation and peptide search by DLS, and proteomics data processing by MeB, YZ, BJP, DLS and RH. Network annotation led by MeB with support from DEG, NJK, RMK and the appendix literature review team. Interactome meta analysis by PB, MeB, HB, MC, ZZCN, IB-H, DM, CH-A, TP, SBR, MCO, YC, JCJC, DJB, SK. Drug selection and annotation by MJO, TAT, SP, YS, ZZ, WS, ITK, JEM, JSC, KL, SAD, JL, LC, SV, JL-L, YiL, X-PH, YoL, PPS, NAW, DK, H-YW, KMS, BKS. Structural modeling by CJPM, KBP, SJG, DJS, RR, XL, SAW, MaB, FSU, TK. Live SARS-CoV-2 virus assays led by KMW (MSSM) and VR (Pasteur) with support from FR, TV, AMK, LM, EM, CK, NSS, DT, DS, SJF, MH. Analysis of SARS-CoV-2 genomic diversity by MalS. Analysis of human gene positive selection by JMY, BM, HSM. Nsp5 cleavage prediction and analysis by MaB and CC with support from DEG. Figure preparation by DEG, MeB, KO, KMW, MJO, DLS TAT, RH, RMK, MK, HB, YZ, ZZ, CJPM, TP, SAW, MaB, MalS, FSU, NAW, DGF, SNF, JDG, DR, TK, PB, KMS, BKS, NJK. Appendix assembled by RMK with support from literature review team: KO, RH, RMK, ALR, BT, HF, JB, KH, MM, MK, PH, JMF, MaE, MarS, MJB, MC, MJM, QL, CJPM, TP, XL, LC, SV, JL-L, YiL, MaB, RT, DAC, JH, JLR, UR, AdS, JN, NJ, SM, SNF. Manuscript prepared by DEG, MeB, KO, MJO, DLS, TAT, RH, RMK, MaE, MarS, MJB, PB, KMS, BKS, NJK. Work supervised by RMS, ADF, OSR, KAV, DAA, MO, MiE, NJ, MVN, EV, AA, OS, CD’E, SM, MJ, HSM, DGF, TI, CSC, SNF, JSF, JDG, AnS, BLR, DR, JT, TK, PB, MV, AG-S, KMS, BKS, NJK.
ISSN:	0028-0836 1476-4687
DOI:	10.1038/s41586-020-2286-9