AziFlu · Mechanism-based influenza neuraminidase inhibitors as antivirals to combat flu infections

Influenza neuraminidases are the primary target for anti-influenza small molecule drugs and are retaining glycosidases that form a transient covalent intermediate during substrate hydrolysis. Oseltamivir (Tamiflu) and Zanamivir (Relenza), the two small-molecule anti-influenza drugs used primarily for early onset treatment of flu infections, inhibit influenza neuraminidases competitively (and thus reversibly). The AziFlu ERC PoC proposal is rooted in our finding that N-acyl Oseltamivir aziridines, or Aziflus, inhibit influenza neuraminidase covalently. They block viral outgrowth in an infected cell model. Our compounds are at least as potent as Oseltamivir. Rather than temporarily disabling influenza neuraminidases, our technology acts in an irreversible, permanent, manner. Our drug candidates are selective for influenza neuraminidases over human neuraminidases, and we propose they may be more effective than existing drugs and may also find use as prophylactics and to treat later disease stages. The AziFlu program will develop our mechanism-based influenza neuraminidase inhibition technology and take the first steps to create a start-up company for bringing the technology to market. To strengthen our scientific case (experimental development, A), we will (A-I) optimise our leads by the synthesis and biochemical evaluation of comprehensive sets of focused analogues; (A-II) design a synthetic route to prepare gram-scale quantities of selected leads; and (A-III) develop assays for in vitro and in vivo target inhibition efficacy, target engagement, and viral outgrowth studies. To prepare for the establishment of a spin-out biotech company (business development, B) to take our leads towards the clinic we will (B-IV) strengthen our intellectual property (IP) position; (B-V) analyse the anti-influenza drug market; and (B-VI) create a start-up biotech company to which the IP will be transferred.