A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Gordon, David E.; Jang, Gwendolyn Μ.; Bouhaddou, Mehdi; Xu, Jiewei; Obernier, Kirsten; Guo, Jeffrey Z.; Swaney, Danielle L.; Tummino, Tia A.; Hüttenhain, Ruth; Kaake, Robyn M.; Richards, Alicia; Tutuncuoglu, Beril; Foussard, Helene; Batra, Jyoti; Haas, Kelsey M.; Modak, Maya; Kim, Minkyu; Haas, Paige; Polacco, Benjamin J.; Braberg, Hannes; Fabius, Jacqueline M.; Eckhardt, Manon; Soucheray, Margaret; Bennett, M. J.; Çakır, Merve; McGregor, Michael; Li, Qiongyu; Naing, Zun Zar Chi; Zhou, Yuan; Peng, Shiming; Kirby, Ilsa T; Melnyk, James E.; Chorba, John S.; Lou, Kevin; Dai, Shizhong; Shen, Wenqi; Shi, Ying; Zhang, Ziyang; Barrio-Hernandez, Iñigo; Memon, Danish; Hernández-Armenta, Claudia; Mathy, Christopher J.P.; Perica, Tina; Pilla, Kala Bharath; Ganesan, Sai J.; Saltzberg, Daniel J.; Ramachandran, Rakesh; Liu, Xi; Rosenthal, Sara Brin; Calviello, Lorenzo; Venkataramanan, Srivats; Liboy-Lugo, José; Lin, Yizhu; Wankowicz, Stephanie A.; Bohn, Markus-Frederik; Sharp, Phillip P.; Trenker, Raphael; Young, Janet M.; Cavero, Devin A.; Hiatt, Joseph; Roth, Theo; Rathore, Ujjwal; Subramanian, Advait; Noack, Julia; Hubert, Mathieu; Roesch, Ferdinand; Vallet, Thomas; Meyer, Björn; White, Kris M.; Miorin, Lisa; Rosenberg, Oren S.; Verba, Kliment A.; Agard, David A.; Ott, Mélanie; Emerman, Michael; Ruggero, Davide; iacute-Sastre, Adolfo Garc; Jura, Natalia; Zastrow, Mark von; Taunton, Jack; Ashworth, Alan; Schwartz, Olivier; Vignuzzi, Marco; Mukherjee, Shaeri; Jacobson, Matthew P.; Malik, Harmit S.; Fujimori, Danica Galonić; Ideker, Trey; Craik, Charles S.; Floor, Stephen N.; Fraser, James S.; Gross, John D.; Šali, Andrej; Kortemme, Tanja; Beltrão, Pedro; Shokat, Kevan M.; Shoichet, Brian K.; Krogan, Nevan J.

doi:10.1101/2020.03.22.002386

Cited by 432 publications

(609 citation statements)

References 166 publications

(94 reference statements)

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“…Camostat is a protease inhibitor approved for the treatment of chronic pancreatitis. Camostat appears to inhibit TMPRSS2 in proteomic and in vitro studies (7,141). A randomized, placebocontrolled trial is underway for this agent in COVID-19 (NCT04321096) (Figure 1).…”

Section: Camostatmentioning

confidence: 99%

COVID-19 for the Cardiologist

Atri

Siddiqi

Lang

et al. 2020

JACC: Basic to Translational Science

268

137

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Highlights-Severe acute respiratory virus-2 (SARS-CoV2), the infection responsible for coronavirus disease-2019 (COVID-19), has spread globally leading to a devastating loss of life. In a few short months, the clinical and scientific communities have rallied to rapidly evolve our understanding of the mechanism(s) of disease and potential therapeutics. -This review discusses the current understanding of the basis virology of SARS-CoV2 and the epidemiology, clinical manifestations, including cardiovascular, and mortality of COVID-19. A detailed review of the viral life cycle and putative mechanism(s) of injury frames the discussion of possible preventative and therapeutic strategies. -The ongoing, unprecedented collective effort will, without a doubt, advance our ability to prevent the spread and optimally care for patients suffering from COVID-19. SummaryThe coronavirus disease-2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2), has reached pandemic status. As it spreads across the world, it has overwhelmed healthcare systems, strangled the global economy and led to a devastating loss of life. Widespread efforts from regulators, clinicians and scientists are driving a rapid expansion of knowledge of the SARS-CoV2 virus and the COVID-19 disease.We review the most current data with a focus on our basic understanding of the mechanism(s) of disease and translation to the clinical syndrome and potential therapeutics. We discuss the basic virology, epidemiology, clinical manifestation, multi-organ consequences, and outcomes. With a focus on cardiovascular complications, we propose several mechanisms of injury. The virology and potential mechanism of injury form the basis for a discussion of potential disease-modifying therapies.

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Section: Camostatmentioning

confidence: 99%

COVID-19 for the Cardiologist

Atri

Siddiqi

Lang

et al. 2020

JACC: Basic to Translational Science

268

137

View full text Add to dashboard Cite

show abstract

“…It is well established that spike (S) protein plays a pivotal role during viral entry into the host cell (Gordon et al, 2020;Ou et al, 2020). The viral entry into the host cells is mediated by the initial binding of the receptor-binding domain (RBD) present at S1 subunit of the S protein to the host ACE2 receptor followed by fusion of the viral spike and host membrane through S2 subunit located on the surface of the S protein.…”

Section: Spike Protein Functionality Predicted To Be Affected By Strumentioning

confidence: 99%

Emergence of multiple variants of SARS-CoV-2 with signature structural changes

Bhowmik

Pal

Lahiri

et al. 2020

Preprint

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This study explores the divergence pattern of SARS-CoV-2 using whole genome sequences of the isolates from various COVID-19 affected countries. The phylogenomic analysis indicates the presence of at least four distinct groups of the SARS-CoV-2 genomes. The emergent groups have been found to be associated with signature structural changes in specific proteins. Also, this study reveals the differential levels of divergence patterns for the protein coding regions. Moreover, we have predicted the impact of structural changes on a couple of important viral proteins via structural modelling techniques. This study further advocates for more viral genetic studies with associated clinical outcomes and hosts' response for better understanding of SARS-CoV-2 pathogenesis enabling better mitigation of this pandemic situation.

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“…Nsp1 has 84.4% identity to the nsp1 of SARS-CoV-1, which is thought to inhibit host gene expression and inhibit the type I interferon response [16]. In addition, a recent proteomics analysis by Gordon et al suggests Nsp1 binds the DNA polymerase Alpha complex, raising the possibility that Nsp1 modulates DNA replication [17]. Nsp2 has 68% identity to Nsp2 of SARS-CoV-1; the function of Nsp2 is less clear, but it is thought to disrupt host signaling [18].…”

Section: Significant Proportions Of Orfs Encoding M S and Orf1a Arementioning

confidence: 99%

Pervasive generation of non-canonical subgenomic RNAs by SARS-CoV-2

Nomburg

Meyerson

DeCaprio

2020

Preprint

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SARS-CoV-2, a positive-sense RNA virus in the family Coronaviridae, has caused the current worldwide pandemic, known as coronavirus disease 2019 or COVID-19. The definition of SARS-CoV-2 open reading frames is a key step in delineating targets for vaccination and treatment for COVID-19. Here, we report an integrative analysis of three independent direct RNA sequencing datasets of the SARS-CoV-2 transcriptome. We find strong evidence for variant open reading frames (ORFs) encoded by SARS-CoV-2 RNA. A variant transcript for the matrix protein (M) lacking its N-terminal transmembrane domain, initiated by a TTG start codon, is produced by a strong transcriptional regulatory sequence (TRS)-mediated junction within the M ORF and represents up to 19% of all M ORFs. Sporadic non-canonical junctions in the spike (S) ORF lead to N-terminal truncations that remove the N-terminal and receptor-binding domains from up to 25% of S ORFs. Surprisingly, nearly all ORFs from ORF1a identified in these transcriptome sequences were variant. These ORFs contain the first 200-800 amino acids of ORF1a and may represent a mechanism to regulate the relative abundance of ORF1a nonstructural proteins. We show there is strong transcriptome and junctional support for variant ORF1a ORFs in independent direct RNA sequencing and short-read RNA sequencing datasets, and further show that up to 1/3 of these ORFs are expected to have C-terminal fusions with downstream genes. Finally, we show that currently unannotated ORFs are abundant in the SARS-CoV-2 transcriptome. Together, these analyses help to elucidate the diverse coding potential of SARS-CoV-2.

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A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Cited by 432 publications

References 166 publications

COVID-19 for the Cardiologist

COVID-19 for the Cardiologist

Emergence of multiple variants of SARS-CoV-2 with signature structural changes

Pervasive generation of non-canonical subgenomic RNAs by SARS-CoV-2

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