Grant: Proof of Principle Program - Phase II

Influenza neuraminidase (also known as a sialidase) is a clinically validated enzyme target for control of influenza infections. Of the four approved drugs that inhibit this enzyme, only Tamiflu (oseltamivir) is orally available, and thus dominates the neuraminidase inhibitor (NAI) market. Tamiflu, and to a lesser extent Relenza (zanamivir), are stockpiled by many countries as first line defence against pandemic influenza in conjunction with vaccination programs. Emerging resistance against Tamiflu, and requirement for delivery of Relenza by inhalation, creates a need for new drugs that evade current and emerging NAI resistance mechanisms and yet can be dosed orally. The Withers laboratory has created the "difluorosialic acids" (DFSAs), a novel class of NAI that is completely inactive against the human enzyme and demonstrates superior in vitro binding kinetics on the viral neuraminidase. DFSAs exhibit a uniquely slow "off-rate" once bound to the target, resulting in a bound residence time that is two orders of magnitude higher than that of Relenza. DFSAs have structural similarity to the natural substrate sialic acid in order to reduce development of resistance. Initial leads have shown activity in vitro, and in cell-based assays against several seasonal influenza A and B strains including a Tamiflu-resistant mutant, resulting in our first patent application (2009). Additional chemistry has yielded new compounds with a greater than ten-fold potency improvement over early leads. We have demonstrated in vitro activity against a broad array of wild type and Tamiflu/Relenza resistant mutants of influenza A and B, and a dose response relationship of efficacy in a mouse model. These compounds are the subject of a second patent application. Funding is sought for further development of this promising class of compounds, to optimize the chemistry to produce an orally available form of DFSA which retains this activity profile in vitro and in vivo.