Grant: Proof of Principle Program - Phase I

The M2 protein is a clinically validated ion channel target essential for virulence of the influenza virus. The only two approved M2 inhibitors, amantadine and rimantadine, were developed in the 1960s and are rarely prescribed due to widespread resistance. Currently, neuraminidase inhibitors (NAI) are the most effective drugs for the control and prevention of influenza. Only Tamiflu (oseltamivir) is orally available, and thus dominates the NAI market. Antiviral drugs are stockpiled by many countries and are essential as first line defence against pandemic influenza in conjunction with vaccination programs. Emerging resistance against Tamiflu, and the requirement for delivery of Relenza by inhalation, has created a need for new drugs that evade current and emerging resistance mechanisms and yet can be dosed orally. Over the last 25 years, no new M2 inhibitors have been developed, likely due to the difficulty in screening this target. Dr. Michel Roberge and Dr. William DeGrado, a structural biologist and leader in the field of M2 structure and M2-amantadine binding, developed a robust quantitative yeast-based assay to identify novel inhibitors of M2. In collaboration with the Centre for Drug Research and Development (CDRD), a screen of 360,000 natural product extracts and pure chemicals was performed and recently yielded a novel, structurally unique inhibitor of the M2 ion channel. A provisional patent application is being drafted covering the lead compound, related compositions and uses thereof and will be filed in September 2013. The compound is three-times more potent than amantadine against wild-type M2, it shows activity against the major amantadine-resistant V27A mutant in the yeast assay and it has antiviral activity in vitro. Moreover, it is easily synthesized and modified, and is likely to be orally bioavailable. These characteristics make the compound an ideal candidate for preclinical development and evaluation in an in vivo model of influenza infection.