Drug Repurposing Identifies Inhibitors of Oseltamivir‐Resistant Influenza Viruses

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Abstract
The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti‐influenza drug. However, oseltamivir‐resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir‐resistant, alternative therapy options are needed. Herein, we show that a structure‐based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir‐resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild‐type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir‐resistance mutation itself caused susceptibility to these drugs.
Funding Information
  • NIH (GM100909, CA21765, HHSN266200700005C)

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