Viral RNA-methyltransferases: function, structure and inhibition

Evžen Bouĝa

Institure of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo namesti 542/2, Praha 6, 16610

boura@uochb.cas.cz

Methyltransferases (MTases) associated with coronaviruses, such as nsp10/16 and nsp14, are responsible for the final stages of RNA-cap formation within the cytoplasm. This cap is crucial for maintaining the stability of viral RNA and plays a pivotal role in evading the innate immune response. Uncapped RNA is swiftly detected by the innate immune system, triggering degradation and activating antiviral defenses. Consequently, the coronaviral MTases have become focal points of extensive scientific investigation. Recently, through the use of X-ray and cryo-electron microscopy techniques, the structures of both enzymes have been elucidated, even in complex with other components of the viral replication machinery. The application of high-throughput screening methods and the design of inhibitors guided by structural insights have resulted in the identification of potent inhibitors targeting these MTases. This talk critically examines the remarkable progress made in the field of coronaviral MTases since the onset of the COVID-19 pandemic. Additionally, it is worth noting that similar investigations into poxviruses' MTases have also contributed significantly to our understanding of viral replication and immune evasion strategies.

This research was funded by the project the National Institute Virology and Bacteriology (Programme EXCELES, Project No. LX22NPO5103) - Funded by the European Union - Next Generation EUand the Grant Agency of Charles University (Grant No. 408422)