Scientists Discover Unexpected Strategy to Halt the Coronavirus Lifecycle

NEW YORK (Reuters Health) – A genetic mechanism hijacked by SARS-CoV-2 to help it reproduce also makes it vulnerable to a new class of drug candidates, early research indicates.

According to the study, published in the journal Genes and Development, cellular reproduction of SARS-CoV-2 requires chemical changes made by the METTL3 protein to RNA. And a molecular inhibitor of METTL3 significantly reduces SARS-CoV-2 replication in cell cultures, as well as a less severe, seasonal coronavirus, HCoV-OC43, which is one cause of the common cold.

“Our results represent the first time a chemical inhibitor of METTL3 has been shown to have an anti-viral effect for coronaviruses, or any virus,” Dr. Ian Mohr, professor in the department of microbiology at NYU Grossman School of Medicine and NYU Langone Health, in New York City, said in a news release.

“This represents a necessary step in drug development, identifies new targets, and reveals an unexpected strategy to halt the coronavirus lifecycle,” Dr. Mohr said.

Coronaviruses that replicate in human cells are known to encode their genomes in RNA, raising the question of whether enzymes that modify RNA could impact the production of viral proteins that allow them to multiply.

“METTL3 is a cellular enzyme subunit/component of a larger protein machine that installs methyl groups onto RNA molecules at a specific chemical position called N-6 on adenosine (or m6A). m6A is the most abundant modification found within the body of mRNAs and its presence or absence can influence how well a gene is expressed,” Dr. Mohr explained in an email to Reuters Health.

“Basically, the presence or absence of m6A at particular sites in an mRNA can impact how stable the mRNA is (i.e. how much time the mRNA lingers inside a cell before being destroyed) and how effectively it can be decoded to provide instructions to produce a protein chain,” he said.

Dr. Mohr’s team discovered that reproduction of SARS-CoV-2 and HCoV-OC43 requires the action of the METTL3 enzyme that installs the m6A methylation on RNA as well as two proteins that bind to methylated RNA (YTHDF1 and YTHDF3).

They further showed that a METTL3 inhibitor developed by U.K.-based Storm Therapeutics can block replication of SARS-CoV-2 and HCoV-OC43.

Compared with an inactive control compound, the highest dose of the METTL3 inhibitor reduced SARS-CoV-2 reproduction by more than 90% and HCoV-OC43 production by more than 80% in human cultured lung cells, they report.

“While it is conceivable that blocking a cellular enzyme like METTL3 might have undesired consequences, it actually turns out that blocking METTL3 did not have any overt toxicity in normal human cells grown in culture under the conditions we tested,” Dr. Mohr told Reuters Health.

“We do not yet have data using the METTL3 inhibitor in a non-human animal model for coronavirus infection, which is an obvious next immediate step,” he added.

“The inhibition of coronaviruses by this molecule is really encouraging but understanding exactly why coronaviruses need m6A RNA modification is important and might enable the design of compounds that work even better,” first author Dr. Hannah Burgess, an assistant research scientist in the department of microbiology at NYU Langone Health, said in the news release.

“We went into it hoping to learn about the differences between the biology of innocuous and pandemic coronavirus infections,” Dr. Angus Wilson, associate professor in the department of microbiology at NYU Langone Health, who also worked on the study, said in the release.

“If anything we found that both share a dependence upon the m6A methylation machinery. That creates the hope that inhibiting METTL3 may also be useful against future pandemic coronaviruses,” Dr. Wilson added.

The study was supported by grants from the National Institute of Allergy and Infectious Diseases, National Institute of General Medical Sciences, National Institutes of Health and the Perlmutter Cancer Center. The authors declare no competing interests.

SOURCE: Genes and Development, online June 24, 2021.

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