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

被引：2406

作者：

Gordon, David E. ^{[1
,2
,3
]}

Jang, Gwendolyn M. ^{[1
,2
,3
]}

Bouhaddou, Mehdi ^{[1
,2
,3
]}

Xu, Jiewei ^{[1
,2
,3
]}

Obernier, Kirsten ^{[1
,2
]}

White, Kris M. ^{[4
,5
]}

O'Meara, Matthew J. ^{[6
]}

Rezelj, Veronica V. ^{[5
]}

Guo, Jeffrey Z. ^{[1
,2
,3
]}

Swaney, Danielle L. ^{[1
,2
]}

Tummino, Tia A. ^{[1
,8
]}

Huttenhain, Ruth ^{[1
,2
,3
]}

Kaake, Robyn M. ^{[1
,2
,3
]}

Richards, Alicia L. ^{[1
,2
,3
]}

Tutuncuoglu, Beril ^{[1
,2
,3
]}

Foussard, Helene ^{[1
,2
,3
]}

Batra, Jyoti ^{[1
,2
,3
]}

Haas, Kelsey ^{[1
,2
,3
]}

Modak, Maya ^{[1
,2
,3
]}

Kim, Minkyu ^{[1
,2
,3
]}

Haas, Paige ^{[1
,2
,3
]}

Polacco, Benjamin J. ^{[1
,2
,3
]}

Braberg, Hannes ^{[1
,2
,3
]}

Fabius, Jacqueline M. ^{[1
,2
,3
]}

Eckhardt, Manon ^{[1
,2
,3
]}

Soucheray, Margaret ^{[1
,2
,3
]}

Bennett, Melanie J. ^{[1
,2
,3
]}

Cakir, Merve ^{[1
,2
,3
]}

McGregor, Michael J. ^{[1
,2
,3
]}

Li, Qiongyu ^{[1
,2
,3
]}

Meyer, Bjoern ^{[1
,2
,3
]}

Roesch, Ferdinand ^{[1
,2
,3
]}

Vallet, Thomas ^{[1
,2
,3
]}

Mac Kain, Alice ^{[1
,2
,3
]}

Miorin, Lisa ^{[1
,2
,3
]}

Moreno, Elena ^{[1
,2
,3
]}

Naing, Zun Zar Chi ^{[1
,2
,3
]}

Zhou, Yuan ^{[1
,2
,3
]}

Peng, Shiming ^{[1
,8
]}

Shi, Ying ^{[1
,3
,9
]}

Zhang, Ziyang ^{[1
,3
,9
]}

Shen, Wenqi ^{[1
,3
,9
]}

Kirby, Ilsa T. ^{[1
,3
,9
]}

Melnyk, James E. ^{[1
,3
,9
]}

Chorba, John S. ^{[1
,3
,9
]}

Lou, Kevin ^{[1
,3
,9
]}

Dai, Shizhong A. ^{[1
,3
,9
]}

Barrio-Hernandez, Inigo ^{[1
,10
]}

Memon, Danish ^{[10
]}

Hernandez-Armenta, Claudia ^{[10
]}

机构：

[1] Univ Calif San Francisco, Quantitat Biosci Inst QBI, San Francisco, CA 94143 USA

[2] J David Gladstone Inst, San Francisco, CA USA

[3] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA

[4] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA

[6] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[7] Inst Pasteur, CNRS UMR 3569, Viral Populat & Pathogenesis Unit, Paris, France

[8] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA

[9] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA

[10] European Bioinformat Inst, European Mol Biol Lab EMBL, Wellcome Genome Campus, Cambridge, England

[11] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[12] Univ Calif San Francisco, UC Berkeley UCSF Grad Program Bioengn, San Francisco, CA 94143 USA

[13] Univ Calif San Diego, Dept Med, Ctr Computat Biol & Bioinformat, San Diego, CA 92103 USA

[14] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA

[15] Univ N Carolina, Chapel Hill Sch Med, Dept Pharmacol, Chapel Hill, NC USA

[16] Univ Calif San Francisco, Biophys Grad Program, San Francisco, CA 94143 USA

[17] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA

[18] Zoic Labs, Culver City, CA USA

[19] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[20] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA

[21] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA

[22] Fred Hutchinson Canc Res Ctr, Div Basic Sci, 1124 Columbia St, Seattle, WA 98104 USA

[23] Univ Calif San Francisco, Dept Microbiol & Immunol, George William Hooper Fdn, San Francisco, CA 98104 USA

[24] Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94143 USA

[25] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[26] Fred Hutchinson Canc Res Ctr, Div Human Biol, 1124 Columbia St, Seattle, WA 98104 USA

[27] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA

[28] Buck Inst Res Aging, Novato, CA USA

[29] Inst Pasteur, Direct Sci, Paris, France

[30] Univ Calif San Diego, Dept Med, Div Genet, San Diego, CA 92103 USA

[31] Icahn Sch Med Mt Sinai, Div Infect Dis, Dept Med, New York, NY 10029 USA

[32] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA

来源：

NATURE | 2020年 / 583卷 / 7816期

关键词：

CORONAVIRUS REPLICATION; NETWORK; VIRUS; IDENTIFICATION; MECHANISMS; INHIBITOR; DISCOVERY; SOFTWARE; DENGUE; MODEL;

D O I：

10.1038/s41586-020-2286-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

A human-SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors. 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(1,2). 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 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.

引用

页码：459 / +

页数：30

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