Key Highlights:
- Researchers from NYU Grossman School of Medicine discovered that coronavirus replication in infected human cells needs chemical alterations to RNA.
- The study demonstrated that STM2457 substantially decreased the replication of the COVID-19 virus.
- The maximum dose of STM2457 reduced the number of infected cells by 90%.
Virus Replication requires Chemical Alterations
A human genetic mechanism used by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, to aid in its transmission also makes it vulnerable to a new class of treatment candidates, according to recent research.
A team led by researchers from NYU Grossman School of Medicine discovered that coronavirus replication in infected human cells needs chemical alterations to RNA, a fundamental type of genetic information, caused by the human protein METTL3. YTHDF1 and YTHDF3, two other human proteins involved in the identification of modified RNA, were also discovered to be crucial in the process.
Using the Virus’s Vulnerabilities Against It
The study demonstrated for the first time that STM2457, a chemical inhibitor of METTL3 developed by Storm Therapeutics Ltd, substantially decreased replication of both pandemic SARS-CoV-2 and a less severe seasonal coronavirus, HCoV-OC43, one cause of the common cold in cell cultures.
Notably, coronaviruses that reproduce within human cells are known to encode the entirety of their genetic instructions in RNA chains. This raises the issue of whether human RNA modification enzymes, such as those that attach methyl groups, may influence viral protein synthesis.
The recent work demonstrated for the first time that the reproduction of SARS-CoV-2 and HCoV-OC43 needs the activity not only of METTL3, the human enzyme that installs m6A methylation on RNA but also of YTHDF1 and YTHDF3, human proteins that bind to this unique arrangement of methylated RNA. Surprisingly, the researchers discovered this m6A mutation in the RNA genomes of both coronaviruses under analysis.
Decreasing replication of the virus
The study examined the effects of STM2457, a METTL3 inhibitor, and STM2120, an inert control drug, on cultures of human lung cells infected with the seasonal coronavirus, or SARS-CoV-2. Following that, the researchers utilized imaging equipment to detect viral infection in hundreds of cells treated with varying dosages of STM2457.
The maximum dose of STM2457 reduced the number of HCoV-OC43 infected cells in culture by more than 80% when compared to the same concentration of the inert control drug, whereas the same dose of STM2457 reduced SARS-CoV-2 reproduction by more than 90%.
Moving forward, the researchers intend to see if STM2457 can interfere with coronavirus replication and avoid severe illness consequences in non-human animals.
