A united and conquering approach finds common weaknesses in the coronavirus | 2020-10-15

“It’s coming. We know it’s coming.”

It was Nemain Crogan’s candid reminder that SARS-CoV-2 was neither the first virus nor the last virus that caused temporary havoc on humankind.

In fact, SARS-CoV-2 was the third coronavirus of the century and sounded a public health warning. This suggests that the entire coronavirus has changed from a nearly harmless drug to a major public health threat for unknown reasons.

Crogan, director of the Institute for Quantitative Biological Sciences (QBI) at the University of California, San Francisco and a senior researcher at the Gladstone Institutes, maximizes the transition by finding common vulnerabilities in SARS. Part of an international team of researchers-CoV-1, MERS-CoV and SARS-CoV-2 have findings not only in the current pandemic, but also in combating possible SARS-CoV-3 outbreaks in the future. I hope it will be useful.

team report Latest results of that approach in the online version on October 15, 2020 Science..

In a previous paper, the team provided a comprehensive one Blueprint Analysis of protein interactions between SARS-CoV-2 and infected host cells, especially Kinase It may provide a draggable target.

In their latest publication, researchers combined proteomics and virological data to identify virus-host protein interactions common to one or both of SARS-CoV-2 and other coronaviruses.

CRISPR-based screening, partly conducted by biotechnology companies Synthego Corp., Identified host proteins that affect the ability of the virus to grow. One of those proteins was the mitochondrial protein Tom70. This is a shuttle that moves other proteins in and out of mitochondria. Tom70 physically interacted with Orf9b on both SARS-CoV-1 and SARS-CoV-2.

The functional consequences of that binding as to how the infection progresses remain completely unclear. However, when the team conducted structural studies, it became clear that Orf9b, the only SARS-CoV-2 protein belonging to the host mitochondria, undergoes a significant shape change when bound to Tom70. did. At a press conference highlighting the important findings of the paper, the difference between the bound and unbound versions of Orf9b was so great that Crogan was two separate proteins, bound and unbound, for targeting purposes. Insisted that there was a possibility.

Real world evidence

In their paper, the team used real-world evidence to search for existing drugs that could affect the clinical course of COVID-19 infection. Collaborators at Aetion Inc. used a database of clinical records of approximately 740,000 US COVID-19 patients (nearly 10% of all diagnosed US cases) and associated better or worse results. I searched for a drug to do.

The findings from that analysis show that the over-the-counter non-steroidal anti-inflammatory drug indomethacin, which inhibits prostaglandin E synthase 2 (PGES2), reduces the risk of hospitalization and the need for hospitalization services, and typical antipsychotics such as haloperidol and chlorpromazine. Suggested that the risk of needing was reduced. Mechanical ventilation of inpatients.

Indomethacin and typical antipsychotics have not been tested in randomized controlled trials. Rather, the strategy was to compare with matched patients taking either celecoxib instead of indomethacin, or atypical instead of typical antipsychotics. The patient group was also small.

However, both the indomethacin target PGES2 and the typical antipsychotic target SigmaR1 receptor interacted with the coronavirus protein in a preclinical study that is also part of the paper.

Whether developing new drugs or diversions, this approach is set up to identify potential host-driven therapies.

Adolfo Garcia-Sastre, director of the Global Health and Emerging Pathogens Institute, said the team’s attempt to identify an approach in which this focus on host proteins works not only for SARS-CoV-2 but also for other coronaviruses. I explained that it was the result of. The virus targeting approach is “very good for certain viruses, but not for the wide spectrum,” he said.

As a co-author, Marc Vignuzzi, a senior researcher at the Pasteur Institute, pointed out that this approach could identify more targets as a whole. “The virus produces 12 proteins, but targets hundreds of host proteins,” he said.