A new class of compounds currently in development against acute myeloid leukemia has been discovered to block coronavirus reproduction in human lung cells.
A new class of compounds currently in development against acute myeloid leukemia has been discovered to block coronavirus reproduction in human lung cells.
In order to reproduce in the body, viruses must hijack some of the natural genetic mechanisms to assist. Coronaviruses encode a complete set of genetic instructions in RNA chains. This led researchers to question whether modifying enzymes would be able to alter the production of viral proteins that enable virus multiplication.
A research team at NYU Grossman School of Medicine found that the reproduction of SARS-CoV-2 and HCoV-OC43, the less severe, seasonal coronavirus that causes the common cold, requires the action of the human enzyme METTL3. METTL3 installs the m6A methylation on RNA, a modification instruction in the genetic instructions for both coronaviruses studied.
This discovery led them to the next step – would inhibiting the action of METTL3 hinder the reproduction of the viruses?
In steps Storm Therapeutics. A spin-out from the University of Cambridge, Storm co-founder Tony Kouzarides worked off the findings showing the role of METTL3 in both establishing disease and leukemia cell differentiation.
Kouzarides team published a paper in April showing the efficacy of a catalytic METTL3 inhibitor in mouse models of AML. Storm’s candidate, STM2457, decreased AML engraftment and increased survival. The drug is expected to enter the clinic early next year.
The NYU Langone team had other ideas for STM2457. Partnered with Storm, STM2457 was tested alongside an inactive control compound on cultures of human lung cells infected with either seasonal “common cold” coronavirus or SARS-CoV-2.
Using imaging to track viral infection on thousands of cells, the cells treated with the highest dose of STM2457 were the proof in the pudding. Cells infected with HCoV-OC43 reduced by more than 80%. Even more encouraging, SARS-CoV-2 reproduction dropped by more than 90% compared to the inactive compound.
“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,” says senior study author Ian Mohr, Ph.D., professor in the Department of Microbiology at NYU Langone Health.
“This represents a necessary step in drug development, identifies new targets, and reveals an unexpected strategy to halt the coronavirus lifecycle.”
The team intends to further investigate the mechanism of m6A modification and its influence on the virus and host gene expression in cells infected with coronaviruses. The next step will be determining if STM2457 can prevent severe disease in animals.
“We went into it hoping to learn about the differences between the biology of innocuous and pandemic coronavirus infections,” says co-corresponding author Angus Wilson, Ph.D., associate professor in the Department of Microbiology at NYU Langone Health. “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.”
