In a study published online in Science, an international team of almost 200 researchers from 14 leading institutions in six countries, including France with the Institut Pasteur and CNRS, studied the three lethal coronaviruses SARS-CoV-2, SARS-CoV-1 and MERS-CoV in order to identify commonly hijacked cellular pathways and detect promising targets for broad coronavirus inhibition. In addition, using the molecular insights gained from this multidisciplinary, systematic study of coronaviruses, the group performed an analysis of medical records of approximately 740,000 patients with SARS-CoV-2 that altered clinical outcomes in these patients to uncover approved therapeutics with potential for rapid deployment. These results demonstrate how molecular information can be translated into real-world implications for the treatment of COVID-19, an approach that can ultimately be applied to other diseases in the future.
"This far-reaching international study elucidates for the first time commonalities and, importantly, vulnerabilities, across coronaviruses, including our current challenge with the SARS-CoV-2 pandemic," said Nevan Krogan, Ph.D., director of the Quantitative Biosciences Institute (QBI) at the School of Pharmacy at UC San Francisco, senior investigator at Gladstone Institutes, and lead investigator of the study. "In unique and rapid fashion, we were able to bridge biological and functional insights with clinical outcomes, providing an exemplary model of a differentiated way to conduct research into any disease, rapidly identify promising treatments and advancing knowledge in the fields of both science and medicine. This body of work was only made possible through the collaborative efforts of senior scientific thought leaders and teams of next-generation researchers at premier institutions across the globe."
In this collaboration, academic and private sector scientists from UCSF, QBI’s Coronavirus Research Group (QCRG), Gladstone Institutes, EMBL's European Bioinformatics Institute (EMBL-EBI) in Cambridge, England, Georgia State University, Icahn School of Medicine at Mount Sinai in New York, Institut Pasteur and CNRS in Paris, Cluster of Excellence CIBSS at the University of Freiburg in Germany, University of Sheffield in the UK, and other institutions as well as the companies Aetion, who makes software for analysis of real-world data and genome engineering company Synthego, participated in the research.
Scientific Revelations from a Cross-Coronavirus Study of Protein Function
Building on their previous work published in both Nature and Cell, the researchers studied SARS-CoV-2, SARS-CoV-1 and MERS-CoV comprehensively, using biochemical, proteomic, genetic, structural, bioinformatic, virological and imaging approaches to identify conserved target proteins and cellular processes across coronaviruses. Leveraging the SARS-CoV-2 map of how the SARS-CoV-2 viral proteins interact with their target human host cell proteins, called an “interactome,” the team built the protein-protein interaction maps for SARS-CoV-1 and MERS-CoV, highlighting several key cellular processes that are shared across all three coronaviruses. These common pathways and protein targets represent high-priority targets for therapeutic interventions for this and future pandemics."Working diligently since the early days of SARS-CoV-2 identification, we came together with the individual strengths of each organization to interrogate the biology and functional activities of these viruses, looking to exploit weaknesses," commented Veronica Rezelj, Ph.D., of Institut Pasteur.
"In our latest study, we augmented our knowledge base by driving down into two additional coronaviruses, elucidating mechanisms across viruses that allow potential therapeutic interventions."
Structural Understanding of a Unique Interaction between viral Orf9b and Human Protein Tom70, Which Normally Supports Antiviral Immune Response
Interestingly, the team found that the mitochondrial outer membrane protein Tom70 interacts with both SARS-CoV-1 and SARS-CoV-2 protein Orf9b. Tom70 is normally involved in the activation of mitochondrial antiviral-signaling protein (MAVS) and is essential for ...
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