Know your enemy

Team uses knowledge of how SARS-CoV-2 infects cells to identify drugs that could combat it

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SAN FRANCISCO—“Fighting fire with fire” is a well-known idiom, and the research community is taking it to heart in the face of COVID-19 as organizations team up to combat a global pandemic with global collaboration. One such effort has united researchers from the University of California, San Francisco (UC San Francisco), Gladstone Institutes, Icahn School of Medicine at Mount Sinai and Institut Pasteur in an effort to identify existing or pending drugs that could be repurposed to combat SARS-CoV-2. The study was led by Dr. Nevan Krogan, director of the Quantitative Biosciences Institute at UC San Francisco and a senior investigator at Gladstone Institutes.
“While a large amount of COVID-19 therapeutic development research focuses on the antivirals and vaccines, we’ve taken a different approach, targeting the human counterparts and vulnerabilities required for viral infection in a human cell,” said Krogan. “Our work leverages approved and development-stage molecules and will help to focus clinical trials toward the most promising agents to combat COVID-19. We also continue to search for additional agents that target the human proteins used by SARS-CoV-2 to expand the armamentarium against the virus.”
The team began by creating a “blueprint” of more than 300 proteins that SARS-CoV-2 takes advantage of to infect and replicate in human cells, then searched for drugs under development and on the market that targeted those proteins. Coronavirus proteins were introduced into human cells in vitro, and as explained by the authors, “[We] cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions.” This led them to 69 molecules with demonstrated binding to those proteins. Forty-seven compounds were tested in SARS-CoV-2-infected cells, as were another 28 compounds proven to act upon two previously identified targets.
Two particular types of drugs—protein translation inhibitors and drugs that modulate proteins known as Sigma1 and Sigma2—showed promise in reducing viral infectivity. Drugs such as zotatifin and ternatin-4/plitidepsin fall into the first category, and both are indicated for cancer treatment; zotatifin is being evaluated as a cancer therapeutic, and ternatin-4/plitidepsin has FDA approval to treat multiple myeloma. As for modulators of Sigma1/Sigma2, their work led them to explore drugs such as progesterone, PB28, PD-144418 and hydroxychloroquine; the antipsychotic drugs haloperidol and cloperazine; siramesine, an antidepressant and anti-anxiety drug; and the antihistamines clemastine and cloperastine.
The research team made a point to note that testing so far has all been in vitro, and none of these drugs should be prescribed or taken to treat COVID-19 until evaluated in human clinical trials.
“While these are early data, we have a high degree of confidence in the results, since similar observations on the antiviral activity of these drugs arose from work done independently at both Mount Sinai and Institut Pasteur. Research at this speed and magnitude could only have been accomplished through a collaborative effort from several scientists at multiple institutions, each bringing unique but complementary skill sets towards a common research goal,” said Dr. Adolfo García-Sastre, professor in the Department of Microbiology and director of the Global Health and Emerging Pathogens Institute of Icahn School of Medicine at Mount Sinai.
García-Sastre and Dr. Marco Vignuzzi, principal investigator in the Viral Populations Unit at Institut Pasteur, led the virological studies.
In addition to identifying potential drugs for future use, this study also touched upon a potential answer for hydroxychloroquine’s adverse cardiac side effects in some studies. While the drug was found to target the Sigma1 and Sigma2 receptors, it was also revealed to bind to hERG, a protein that plays a pivotal role in regulating electrical activity in the heart.
Along those lines, their research led them to earmark another drug for further study—not as a helper, but as a hindrance. Dextromethorphan, a cough suppressant, was found to boost SARS-CoV-2 viral infection in the lab.
Of the proteins identified as targets for SARS-CoV-2 infection, several were “implicated in innate immune signaling,” which could help explain the erratic immune system responses and cytokine storms often seen in patients with COVID-19.
“We believe there is great potential in systematically exploring the host dependencies of the SARS-CoV-2 virus to identify other host proteins already targeted with existing drugs. Therapies targeting the host-virus interface, where mutational resistance is arguably less likely, could potentially present durable, broad-spectrum treatment modalities,” the authors argued in their paper.
They added that they have also mapped host-pathogen interfaces in others viruses as well, such as Ebola, Dengue, Zika, herpesvirus, hepatitis C, tuberculosis, chlamydia, enteroviruses, HIV, HPV and West Nile fever.
“Excitingly, we have uncovered both shared and unique mechanisms in which these pathogens co-opt the host machinery during the course of infection. Although host-directed therapy is often not explored for combatting pathogenic infections, it would be interesting to use this information to identify host factors that could serve as targets that would harbor pan-pathogenic activity so that when the next virus undergoes zoonosis, we will have treatment options available,” the researchers concluded.

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