A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing
Posted on: 9 April 2020 , updated on: 10 April 2020
Preprint posted on 27 March 2020
Article now published in Nature at http://dx.doi.org/10.1038/s41586-020-2286-9
Can the SARS-CoV-2 pandemic be slowed? Systematic discovery of the SARS-CoV-2 human interactome.
Selected by Robert Mahen
Categories: biochemistry, cell biology, genetics, genomics, molecular biology, pathology, physiology, synthetic biology, systems biology
SARS-CoV-2, the causative agent of COVID-19, has infected in excess of 1.5 million people worldwide and is implicated in >90000 deaths. The pandemic has forced half the planet into lockdown, with further socioeconomic costs yet to be fully incurred. There are no efficient COVID-19 antivirals or vaccines and few people are immune thus far. The scientific community – and indeed the world – is looking in haste for treatments with which to slow the pandemic. It is, as British prime minister Boris Johnson put it, the health crisis of a generation.
How viruses hijack cellular systems is a fascinating cell biological question. With the SARS-CoV-2 pandemic it is now an issue viscerally impacting our daily lives.
Key findings
Gordon et al., have produced the first systematic analysis of which human proteins SARS-CoV-2 may interact with during infection. Almost all SARS-CoV-2 viral genes were cloned and expressed in human HEK293T cells as 2xStrep-tag fusion proteins. The 27 tagged viral proteins were analysed with affinity-purification mass spectrometry, isolating them from lysates and determining the human proteins associating with them (Figure 1). Thus, 332 human proteins interacting with SARS-CoV-2 viral genes were discovered, providing a first SARS-CoV-2 human protein interactome.
Figure 1. Selected panels taken directly from Gordon et al., 2020. (a) Table of the SARS-CoV-2 proteins, including molecular weight, sequence similarity with the SARS-CoV homolog, and inferred function based on the SARS-CoV homolog. (b) Experimental workflow for expressing each 2xStrep tagged SARS-CoV-2 fusion protein in biological triplicate in HEK293T cells, followed by affinity purification-mass spectrometry, and PPI scoring to identify 332 high confidence protein-protein interactions. Made available by a CC-BY 4.0 international license.
What does this interactome tell us about the biology of the virus? Gene ontology enrichment analysis showed that the viral interactome involves a variety of cellular processes (Figure 2), including transcription, translation, ubiquitination regulation, nuclear import and mitochondrial function. Some SARS-CoV-2-human protein-protein interactions appear to be related to viral immune evasion, such as interactions of Nsp13 with interferon signalling components or the interaction of structural protein N with stress granule protein G3BP1. Others may be related to viral entry and replication, with strong representation from intracellular membrane traffic (Nsp7 with Rabs, Nsp10 with AP2, E with AP3, and Orf3a with the HOPS complex). Coronaviruses gain cellular entry through the S glycoprotein which mediates viral and host cell membrane fusion events (Li et al., 2003). S protein was found associated with the GOLGA7-ZDHHC5 acyl-transferase complex, which may mediate S palmitoylation on its cytosolic tail, as has already been shown for SARS-CoV-1 (Petit et al., 2007).
Whilst these interactions suggest how intracellular membrane trafficking pathways may be rewired to favour the virus, other viral protein interactions are equally interesting yet require more imagination to understand their relevance. For example, Nsp13 interacts with multiple different proteins involved in microtubule-based processes, both at the centrosome, (CEP250, CEP68, AKAP9) and Golgi (Golgins). Why Nsp13 – the viral helicase/triphosphatase (Ivanov et al., 2004) – binds to multiple different centrosome associated genes is just one of a number of interesting questions amongst this dataset.
Figure 2. A selected panel from Gordon et al., 2020. Gene Ontology (GO) enrichment analysis performed on the human interacting proteins of each viral protein. The top GO term of each viral protein was selected for visualization. Made available by a CC-BY 4.0 international license.
Gordon et al., searched for small molecules targeting the newly identified SARS-CoV-2 human protein interactome, using chemoinformatics databases and analyses, to find 62 drugs targeting the virus-host interactome. Notably, 27 of these are already FDA approved, providing a realistic possibility of using them in patients rapidly. Included in this list are some possible COVID-19 treatments that have been widely discussed in the weeks since the pandemic erupted, such as chloroquine (Wang et al., 2020).
Why I chose this preprint
This preprint identifies crucial SARS-CoV-2 protein-protein interactions which can now be further tested for their relevance to the therapy and biology of COVID-19. It provides insight into how the virus is currently wreaking havoc with cellular systems, inside hundreds of thousands of infected individuals worldwide.
The collaborative and open nature of this work, and speed at which it has been produced is impressive – the first COVID-19 cases were around mid-December 2019 (Zhou et al., 2020) and the first version of this work was shared 22nd March 2020. This preprint illustrates how preprint servers are a major medium by which scientific work can be rapidly disseminated and evaluated, and how fast knowledge can be gained in response to a crisis.
Questions
There are a significant number of biological processes represented in the interactome, some of which suggest intuitive hypotheses for future work, and others which seem more complex to understand. Is there a part of this network which most surprised you in the context of protein-protein interactions found in other viruses?
You looked at the similarity of the SARS-CoV-2 interactome to ten other viruses. Would a close comparison to a matched SARS-CoV-1 dataset be informative?
You used individually expressed viral genes. Would you expect similar results in the context of a whole virus? For example, the S protein seems to have relatively few interactors, and I’m curious as to whether this could be related to differential functions as a heterologously expressed protein versus a virion?
Given the impressive size and speed of this collaborative effort, I’m particularly curious to know what your next steps might be. You mention genetic and compound screening to verify the results?
References
Ivanov KA, Thiel V, Dobbe JC, van der Meer Y, Snijder EJ, Ziebuhr J. Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase. J Virol. 2004 Jun;78(11):5619-32.
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27;426(6965):450-4.
Petit CM, Chouljenko VN, Iyer A, Colgrove R, Farzan M, Knipe DM, Kousoulas KG. Palmitoylation of the cysteine-rich endodomain of the SARS-coronavirus spike glycoprotein is important for spike-mediated cell fusion. Virology. 2007 Apr 10;360(2):264-74.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270-273.
doi: https://doi.org/10.1242/prelights.18355
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March in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) cancer biology 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics and genomics 6) other
| List by | Girish Kale et al. |
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
Early 2025 preprints – the genetics & genomics edition
In this community-driven preList, a group of preLighters, with expertise in different areas of genetics and genomics have worked together to create this preprint reading list. Categories include: 1) bioinformatics 2) epigenetics 3) gene regulation 4) genomics 5) transcriptomics
| List by | Chee Kiang Ewe et al. |
End-of-year preprints – the genetics & genomics edition
In this community-driven preList, a group of preLighters, with expertise in different areas of genetics and genomics have worked together to create this preprint reading list. Categories include: 1) genomics 2) bioinformatics 3) gene regulation 4) epigenetics
| List by | Chee Kiang Ewe et al. |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University
This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.
| List by | Nándor Lipták |
20th “Genetics Workshops in Hungary”, Szeged (25th, September)
In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf
| List by | Nándor Lipták |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
| List by | Jesus Victorino |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
Also in the molecular biology category:
Keystone Symposium – Metabolic and Nutritional Control of Development and Cell Fate
This preList contains preprints discussed during the Metabolic and Nutritional Control of Development and Cell Fate Keystone Symposia. This conference was organized by Lydia Finley and Ralph J. DeBerardinis and held in the Wylie Center and Tupper Manor at Endicott College, Beverly, MA, United States from May 7th to 9th 2024. This meeting marked the first in-person gathering of leading researchers exploring how metabolism influences development, including processes like cell fate, tissue patterning, and organ function, through nutrient availability and metabolic regulation. By integrating modern metabolic tools with genetic and epidemiological insights across model organisms, this event highlighted key mechanisms and identified open questions to advance the emerging field of developmental metabolism.
| List by | Virginia Savy, Martin Estermann |
April in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell cycle and division 3) cell organelles and organisation 3) cell signalling and mechanosensing 4) (epi)genetics
| List by | Vibha SINGH et al. |
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
February in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry and cell metabolism 2) cell organelles and organisation 3) cell signalling, migration and mechanosensing
| List by | Barbora Knotkova et al. |
Community-driven preList – Immunology
In this community-driven preList, a group of preLighters, with expertise in different areas of immunology have worked together to create this preprint reading list.
| List by | Felipe Del Valle Batalla et al. |
January in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics/gene expression
| List by | Barbora Knotkova et al. |
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |
Also in the pathology category:
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
COVID-19 / SARS-CoV-2 preprints
List of important preprints dealing with the ongoing coronavirus outbreak. See http://covidpreprints.com for additional resources and timeline, and https://connect.biorxiv.org/relate/content/181 for full list of bioRxiv and medRxiv preprints on this topic
| List by | Dey Lab, Zhang-He Goh |
1
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
| List by | Pablo Ranea Robles |
Also in the physiology category:
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Also in the synthetic biology category:
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
| List by | Jesus Victorino |
Antimicrobials: Discovery, clinical use, and development of resistance
Preprints that describe the discovery of new antimicrobials and any improvements made regarding their clinical use. Includes preprints that detail the factors affecting antimicrobial selection and the development of antimicrobial resistance.
| List by | Zhang-He Goh |
Advances in Drug Delivery
Advances in formulation technology or targeted delivery methods that describe or develop the distribution of small molecules or large macromolecules to specific parts of the body.
| List by | Zhang-He Goh |
Also in the systems biology category:
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
Single Cell Biology 2020
A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.
| List by | Alex Eve |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
Pattern formation during development
The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.
| List by | Alexa Sadier |