Study finds new oral drugs can prevent resistant variants of COVID-19

Researchers have found that a new class of oral drugs that act directly on human cells can inhibit pathogenic strains of SARS-CoV-2. (CREDIT: Creative Commons)

The constant evolution of new variants of COVID-19 forces clinicians to have multiple treatments for drug-resistant infections in their arsenal. Researchers have found that a new class of oral drugs that act directly on human cells can inhibit a wide range of SARS-CoV-2 pathogenic strains.

In their recently published study, the team discovered a novel mechanism by which the gene that expresses angiotensin-converting enzyme-2 (ACE-2) — the cellular receptor that SARS-CoV-2 binds to so it can enter and infect cells — is turned on. They also found that a class of oral drugs currently in human clinical trials could block this pathway and potentially be a therapeutic option for all SARS-CoV-2 variants, as well as any emerging SARS-like viruses. The team published their findings in the journal Nature Genetics.

“Due to drug-resistant options, we are forced to use only one drug, Paxlovid, of our oral options,” says Craig Wilen, MD, assistant professor of laboratory medicine and immunobiology, and Fellow of the Yale Cancer Society. Center. “Targeting these core regulatory complexes complements existing approaches and fills the need for a new class of drugs that can be used to combat drug resistance and infections.” Wilen and Sigall Kadoc, PhD, from the Dana-Farber Cancer Institute, were co-authors of the study.

Researchers identify mSWI/SNF complexes as potential antiviral targets as well

In a previous study published in 2021, Wilen’s team at Yale University performed genetic screening to determine the host factors that are required for SARS-CoV-2 infection. One key player was the non-mammalian non-fermentable switch/sucrose chromatin remodeling complex (mSWI/SNF, also called BAF), a group of over a dozen highly conserved proteins that allow certain genes to be turned on.

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“At that time, I had never heard of it in the context of a viral infection, and we couldn’t understand why it was important for coronaviruses,” Wilen says. So the group teamed up with experts on the complex, the Kadoch Lab at the Dana-Farber Cancer Institute and Harvard Medical School, to find out how the protein complex works to make cells susceptible to infection, and whether new drugs against these complexes can stop growth. viral infection.

At the time they began working together, the U.S. Food and Drug Administration approved six emergency-use monoclonal antibody treatments, but none of these treatments work against the latest Omicron variants. This leaves clinicians with remdesivir, which can only be administered intravenously, limiting its use; molnupiravir, an oral drug that works similarly to remdesivir but is only 30 percent effective; and Paxlovid, an oral antiviral drug that works by inhibiting viral protease. Paxlovid, Vilen says, is the backbone of modern treatment.

“It’s a great drug that works well, but there’s been some resistance to it,” he says. “And it’s currently the only drug in our toolbox that we can give orally.” The decline in effective treatments further highlights the urgent need for a new class of drugs to be added to the toolbox, and ideally ones that are less susceptible to fast-acting resistance mechanisms.

Blocking mSWI/SNF protects cells from SARS-CoV-2

First, the team found that disrupting the mSWI/SNF complexes prevents the virus from entering human cells. Since mSWI/SNF is known to regulate gene switching on and off, they hypothesized that it may also play a role in ACE-2 receptor activation. They then unraveled its mechanism: mSWI/SNF binds to another protein called HNF1A, a transcription factor that directs it to the gene encoding ACE-2. After the destruction of the mSWI/SNF complexes, the cell could no longer produce ACE-2 and became resistant to infection by any virus using this receptor. This includes many coronaviruses.

Small molecule inhibitors targeting mSWI/SNF have already been developed by Kadoch-founded Foghorn Therapeutics and are in Phase I clinical trials as a therapeutic agent for several cancers. Wilen and Cadoc found that this class of drugs was effective against several variants of SARS-CoV-2, including a remdesivir-resistant strain isolated from a Yale patient, without any side effects on the cell. “This is evidence that this can be a really important first or second line tool to fight drug resistance,” Wilen says.

“Furthermore, this suggests a broad potential for pharmacological modulation of chromatin remodeling complexes in many diseases,” says Kadok. “These molecular machines are at the top of the pyramid in driving gene expression programs that go awry in many different human diseases – we’re just at the tip of the iceberg in identifying and studying their usefulness.”

Many of these viruses use ACE-2 as their receptor, meaning this new research could hold the key to slowing or stopping the next outbreak. (CREDIT: Creative Commons)

Vilen believes the drugs in these clinical trials could potentially be repurposed to suppress both current and future coronaviruses. In addition, Wilen and Cadoc hope the work will help understand why certain people and certain cell types may be more susceptible to the coronavirus than others. “Further work is needed to understand the biology behind why some people have no symptoms and others have severe infection and death,” Wilen says.

COVID-19 will not be the last major viral outbreak. Vilena’s lab is studying coronaviruses circulating in wild bats, which he believes pose the greatest risk of infecting humans and causing the next pandemic. Many of these viruses use ACE-2 as their receptor, meaning this new research could hold the key to slowing or stopping the next outbreak. “We will have another pandemic, whether in a few years or in a decade. And we are not ready for that,” he says. “The best way to prepare is to prepare as many vaccines and drugs as possible so that we can fight the outbreak early with maximum efficiency.”

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Note: Materials provided above by Yale University. Content can be edited for style and length.

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