Poster Presentation Australian Society for Microbiology Annual Scientific Meeting 2024

Novel oseltamivir derivatives demonstrated in vitro activity against influenza A neuraminidases (#118)

Qingyu Zou 1 , Jiqing Ye 2 3 , Xiao Yang 1 , Cong Ma 3
  1. Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
  2. School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
  3. State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China

Influenza is a highly contagious respiratory disease that is mainly caused by influenza A virus. Seasonal and pandemic outbreaks of influenza results in millions of people being infected and poses a serious threat to global public health. Current prevention and treatment methods involve vaccines and over-the-counter medications such as oseltamivir, zanamivir, and the recently FDA-approved baloxavir marboxil. However, the drawbacks of current medications, such as emergence of oseltamivir resistance and low oral bioavailability of zanamivir, make development of new anti-influenza agents necessary.

A key enzyme on influenza A virus is neuraminidase, which is responsible for the release of virus particles from infected host cells. Targeting a cavity adjacent to the active site on neuraminidase, a total of 26 derivative compounds were synthesized based on the chemical structure of neuraminidase inhibitor oseltamivir. The inhibitory activities of the compounds against H3N2 neuraminidase were evaluated using fluorescence-based neuraminidase inhibition assays. The two compounds with the highest activities were further tested with neuraminidases from different influenza strains. Moreover, cytotoxicity of the compounds was also assessed and MDCK cell-based ELISA was employed to determine their effectiveness against H3N2 virus-infected cells.

All compounds showed good inhibitory activities against H3N2 neuraminidase. Two compounds with the lowest half maximal inhibitory concentration (IC50), 5b and 5f, also demonstrated efficacy against neuraminidases from H1N1 and H5N1 strains. Additionally, they offered excellent protection to MDCK cells from H3N2 infection, comparable to that of oseltamivir and zanamivir, while not exhibiting toxicity to MDCK cells. The results suggest that our compounds have the potential to be utilized in clinical settings, particularly for curing H3N2 infections. Further studies will involve testing of representative compounds with a mouse infection model to evaluate their in vivo effectiveness.

Our research serves as a basis for the development of novel anti-influenza compounds based on rational drug design. Ultimately, we are aiming to procure additional therapeutic options to combat the constant emergence of new seasonal and pandemic influenza strains.65f3cb64048b8-Copy+of+(H3N2)+Perth+5b+5f+(nM).jpg

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