In research published October 15 in scienceAn 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 to identify frequently hijacked cell pathways and identify promising targets for a broad coronavirus Inhibition.
In addition, using the molecular insights from this multidisciplinary, systematic investigation of coronaviruses, the group analyzed the medical records of approximately 740,000 patients with SARS-CoV-2 and evaluated the clinical outcomes in these patients to uncover approved therapeutics with potential for rapid deployment. These results show how molecular information can be translated into real-world implications for treating COVID-19, an approach that can ultimately be applied to other diseases in the future.
“This far-reaching international study highlights for the first time similarities and, above all, weaknesses between coronaviruses, including our current challenge with the SARS-CoV-2 pandemic,” said Dr. Nevan Krogan, director of the Quantitative Biosciences Institute (QBI) at the UC San Francisco School of Pharmacy, lead investigator at the Gladstone Institutes, and lead investigator on the study. “In a unique and fast way, we have been able to combine biological and functional findings with clinical results and provide an exemplary model for a differentiated way to research any disease, quickly identify promising treatments and expand knowledge in the fields of science and medicine. This work has only been made possible through the collaboration of high-level scientific thought leaders and next-generation research teams at leading institutions around the world. ”
The collaboration included scientists from the academic and private sectors of the UCSF, the Coronavirus Research Group (QCRG) of the QBI, the Gladstone Institute, the European Bioinformatics Institute (EMBL-EBI) of the EMBL in Cambridge, England, Georgia State University and the Icahn School of Medicine at Mount Sinai in New York, Pasteur Institute in Paris, the CIBSS Cluster of Excellence at the University of Freiburg in Germany, University of Sheffield in Great Britain and other institutions, as well as from Aetion, which produces software for the analysis of real data, and genome engineering company Synthego .
Cross Coronavirus Study of Protein Function
Building on previous work published in both nature and cellResearchers extensively studied SARS-CoV-2, SARS-CoV-1 and MERS-CoV using biochemical, proteomic, genetic, structural, bioinformatic, virological, and imaging techniques to identify conserved target proteins and cellular processes across coronaviruses. Using a SARS-CoV-2 map or an “interactome” that documents how SARS-CoV-2 proteins interact with their target proteins in human host cells, the team created protein-protein interaction maps for SARS-CoV-1 and MERS-CoV. Highlighting several key cellular processes that are shared by all three coronaviruses. These common pathways and protein targets represent high priority targets for therapeutic interventions for this and future pandemics.
“Since the inception of SARS-CoV-2 identification, we have worked diligently with the individual strengths of each organization to study and exploit the biological and functional activities of these viruses,” said Veronica Rezelj, PhD from the Pasteur Institute. “In our most recent study, we expanded our knowledge base by using two additional coronaviruses to elucidate the mechanisms of the different viruses that enable potential therapeutic interventions.”
Unique interaction between two viruses and a human protein
The team found that a human protein called Tom70 interacts with a protein called Orf9b, which is found in both the SARS-CoV-1 and SARS-CoV-2 viruses. Tom70 is normally involved in activating a signaling protein known as MAVS, which is essential for an innate antiviral immune response. The team showed that when Orf9b binds to Tom70, it inhibits Tom70’s interaction with a protein called Hsp90, which plays a key role in the interferon pathway and induces protective cellular self-destruction when cells become infected with a virus.
In a collaboration of more than 60 QCRG scientists under the direction of QBI colleagues Klim Verba, PhD, and Dr. Oren Rosenberg, MD, PhD, the structure of Orf9b bound to the active site of Tom70 was determined by cryoelectron microscopy (cryoEM) at near-atomic resolution as well as highly unusual protein-protein interactions. The functional importance and regulation of these Orf9b-Tom70 interactions needs further investigation. However, since these interactions have been observed in both SARS-CoV-1 and SARS-CoV-2 viruses, a deeper understanding of these processes as a pan value could be useful. therapeutic target of the coronavirus.
Potential targets for clinically approved therapeutics
Using the three coronavirus interactomes as a guide, the team performed CRISPR and RNA interference (RNAi) knockouts of the putative host target proteins of each virus and examined how the loss of these proteins increased the ability of SARS-CoV-2 Infection of human cells.
They found that 73 of the proteins studied were important for this virus to replicate and used this list to prioritize drug target scoring. Among these was the receptor for the inflammatory signaling molecule IL-17, which has been identified in numerous other studies as an important marker for the severity of COVID-19 disease; Prostaglandin E synthase 2 (PGES2), which functionally interacts with the Nsp7 protein in all three viruses; and sigma receptor 1, which interacts with Nsp6 in both SARS-CoV-1 and SARS-CoV-2.
Armed with this knowledge, the group performed a retrospective analysis of the medical billing data of approximately 740,000 people who had tested positive or were considered positive for SARS-CoV-2.
In the outpatient setting, SARS-CoV-2 positive patients newly prescribed indomethacin, a nonsteroidal anti-inflammatory drug (NSAID) targeting PGES-2, were less likely to require hospitalization or inpatient care than CoV-2 positive new users of celecoxib, a NSAID that does not target PGES-2.
In the inpatient setting, using the medical billing data again, the group compared the effects of two classes of antipsychotics on COVID-19 results. In cell culture experiments, the team found that a class known as “typical” antipsychotics binds sigma-1 receptors and also has antiviral activity. No antiviral activity was seen with atypical antipsychotics used for the same indication. Half as many SARS-CoV-2-positive patients who were newly prescribed typical antipsychotics required mechanical ventilation compared to new users of atypical antipsychotics. Typical antipsychotics can have significant side effects, but there are other drugs that target sigma receptor 1 and more are under development.
“It’s important to note that the number of patients taking each of these compounds are small, non-interventional studies,” said Krogan. “Nonetheless, they are convincing examples of how molecular insights can quickly generate clinical hypotheses and prioritize candidates for prospective clinical studies or future drug development. A careful analysis of the relative benefits and risks of these therapeutics should be performed before prospective studies or interventions are considered. ”
Pedro Beltrao, PhD, group leader at EMBL’s European Bioinformatics Institute, said, “These analyzes show how biological and molecular information translates into real-world implications for the treatment of COVID-19 and other viral diseases. After more than a century of relatively harmless coronaviruses, we have had three deadly coronaviruses in the past 20 years. By looking at the species, we can predict pan-coronavirus therapeutics that may be effective in treating the current pandemic. We believe that this also offers therapeutic prospects for a future coronavirus. ”
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