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In a study published online at Sciences Today, an international team of nearly 200 researchers from 14 leading institutions in six countries studied the three deadly coronaviruses SARS-CoV-2, SARS-CoV-1, and MERS-CoV in order to identify commonly hijacked cellular pathways and detect promising targets. for a wide variety of coronavirus inhibition.
In addition, using the molecular insights gained from this multidisciplinary and systematic study of coronavirus, the group conducted an analysis of the medical records of approximately 740,000 SARS-CoV-2 patients that altered clinical outcomes in these patients to discover approved therapies 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 wide-ranging international study clarifies for the first time the commonalities and, more importantly, the vulnerabilities, among 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 UC San Francisco School of Pharmacy, principal investigator for the Gladstone Institutes and principal investigator on the study. “In a unique and rapid way, we were able to unite biological and functional insights with clinical outcomes, providing an exemplary model for a differentiated way to conduct research on any disease, quickly identify promising treatments, and advance knowledge in the fields of science and technology. medicine … This body of work was only possible thanks to the collaborative efforts of senior scientific leaders and next-generation teams of researchers at leading institutions around the world. “
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 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 Aetion companies, which manufactures software for the analysis of real world data and enterprise Synthego Genome Engineering, participated in the research.
Scientific insights from a coronavirus crossover study on protein function
Based on his previous work published in both Nature Y Cell, 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 in coronaviruses. . Taking advantage of the SARS-CoV-2 map of how the SARS-CoV-2 viral proteins interact with their target human host cell proteins, called the “interactome,” the team built the protein-protein interaction maps for the SARS- CoV-1 and MERS. -CoV, highlighting several key cellular processes that are shared among the three coronaviruses. These common pathways and protein targets represent high priority targets for therapeutic interventions for this and future pandemics.
“Working diligently from the early days of the identification of SARS-CoV-2, we join with the individual strengths of each organization to interrogate the biology and functional activities of these viruses, seeking to exploit the weaknesses,” said Veronica Rezelj, Ph. D. , from the Institut Pasteur. “In our latest study, we increased our knowledge base by narrowing down to two additional coronaviruses, elucidating the mechanisms through viruses that allow possible therapeutic interventions.”
Structural understanding of a unique interaction between the Orf9b virus and the human Tom70 protein, which normally supports the antiviral immune response
Interestingly, the team discovered that the mitochondrial outer membrane protein Tom70 interacts with the Orf9b protein of SARS-CoV-1 and SARS-CoV-2. Tom70 normally participates in the activation of the mitochondrial antiviral signaling protein (MAVS) and is essential for an innate antiviral immune response. Orf9b, by binding to the Tom70 substrate recognition site, inhibits the interaction of Tom70 with heat shock protein 90 (Hsp90), which is key to its role in the interferon pathway and the induction of apoptosis after virus infection .
In a collaboration between more than 60 scientists at the QCRG led by Klim Verba and Oren Rosenberg at QBI, the structure of Orf9b bound to the Tom70 active site was determined using cryoelectron microscopy (cryoEM) at remarkable three-angle resolution. A remarkable and rare find showed that Orf9b, when on its own, forms a dimer and structurally a beta sheet, but exists as an alpha helix when attached to Tom70. Using the structural image of the bound proteins, the scientists were able to discover that a key residue in the interaction with Hsp90 moves out of position, suggesting that Orf9b may modulate key aspects of the immune response, interferon, and apoptosis signaling. via Tom70. The functional importance and regulation of the Orf9b-Tom70 interaction require further experimental elucidation. However, this interaction, which is conserved between SARS-CoV-1 and SARS-CoV-2, could have value as a therapeutic target for pan-coronavirus.
Pathway Goals for Potential Clinically Approved Therapies
Using the three coronavirus interactomes as a guide, the team performed RNA and CRISPR (RNAi) interference deletions from the putative host proteins of each virus and studied how the loss of these proteins altered the ability of SARS-CoV-2 to infect cells. human. They determined that 73 of the proteins studied were important for virus replication and used this list to prioritize the evaluation of drug candidates. These include the receptor for the inflammatory signaling molecule IL-17, which has been identified in numerous studies as an important indicator of the severity of the disease; prostaglandin E synthase 2 (encoded by PTGES2), which functionally interacts with the Nsp7 protein in all three viruses; and the sigma 1 receptor, a SARS-CoV-1 and SARS-CoV-2 Nsp6 interactor, which the group previously showed as a promising drug target in the laboratory setting.
Armed with this knowledge, the group conducted a retrospective analysis of the medical billing data of approximately 740,000 people who tested positive for SARS-CoV-2 or were presumptive positive.
In the outpatient setting, new users of indomethacin, a non-steroidal anti-inflammatory drug (NSAID) that targets PGES-2, positive for SARS-CoV-2, were less likely than new users of celecoxib, an NSAID that does not does. target PGES-2, to require hospitalization or inpatient services.
In the hospital setting, again taking advantage of medical billing data, the group compared the effectiveness of typical antipsychotics, namely haloperidol, which has activity against the sigma 1 receptor, versus atypical antipsychotics, which do not. Half of the new users of typical antipsychotics compared with new users of atypical antipsychotics progressed to the point of requiring mechanical ventilation. Typical antipsychotics can have significant adverse effects, but other drugs that target the sigma 1 receptor exist and are still being developed.
“It’s critical to note that the number of patients taking each of these compounds represents small, non-interventional studies,” Dr. Krogan commented. “Nonetheless, they are powerful examples of how molecular knowledge can rapidly generate clinical hypotheses and help prioritize candidates for prospective clinical trials or future drug development. A careful analysis of the relative benefits and risks of these therapies should be performed before considering prospective studies or interventions. “
“These analyzes demonstrate how biological and molecular information is translated into real-world implications for the treatment of COVID-19 and other viral diseases,” said Pedro Beltrao, Ph.D., group leader from EMBL’s European Bioinformatics Institute. “After more than a century of relatively harmless coronaviruses, in the last 20 years we have had three coronaviruses that have been fatal. By looking across species, we have the ability to predict pan-coronavirus therapeutics that may be effective in treating the current pandemic, which we believe will also offer therapeutic promise for a future coronavirus. “
Source:
University of California – San Francisco
Magazine reference:
Gordan, DE, et al. (2020) Comparative coronavirus-host protein interaction networks reveal panviral disease mechanisms. Sciences doi.org/10.1126/science.abe9403.
