Research progress in polymerase basic 2 inhibitors of influenza virus RNA

Seasonal influenza is an acute viral infection that spreads easily from person to person and is currently one of the major respiratory infections that pose a threat to human health. To date, the prevention and treatment of influenza has been mainly based on vaccination and the development of antiviral drugs. At present, the anti-influenza virus drugs used in clinical include matrix protein 2 inhibitors (such as amantadine), neuraminidase inhibitors (such as oseltamivir), endonuclease inhibitors(such as baloxavir), polymerase inhibitors(such as favipiravir), all of which have shown widespread resistance. The research and development of anti-influenza virus drugs with novel mechanisms and no cross-resistance to existing drugs is an effective means to solve the medical problem of seasonal influenza treatment, which has not yet been completely solved, and to deal with large-scale influenza outbreaks. The polymerase basic 2(PB2)of influenza virus RNA is not prone to drug resistance due to its high conserved nature among different influenza viruses, making it a very attractive drug target. At present, the research and development of PB2 inhibitors has become a hot spot for anti-influenza virus drugs, especially the research on the star molecule Pimodivir and its analogues has attracted great attention. Although Pimodivir was terminated in phase Ⅲ clinical trials due to its unsatisfactory efficacy, the binding pattern and structure-activity relationship between PB2 protein and small molecules revealed during its research process laid a solid foundation for the further development of this class of drugs. This article reviews the research progress of PB2 inhibitors in medicinal chemistry in the past 10 years, and puts forward the prospect of this drug research field.