Grant: Project Grant

The death-cap mushroom, A. phalloides produces a toxin known as amanitin, which has a unique and desirable ability to kill both growing and quiescent cells, with the latter being most challenging for most payloads and therapeutics. This uniform toxicity is exciting for use in targeted cancer therapy since not all cancer cells grow at the same rate. It is known that amanitin can be targeted to cancer by using either cancer-homing peptides or antibodies. However, until our CIHR-supported grant (2018-2022) led to the first synthesis of this toxin, there had been no viable route to synthetic amanitin and essentially no sophisticated understanding as to what parts of the toxin are essential for toxicity and what parts can be modified chemically to target it for therapeutic use. In 2018, we published the first synthesis of amanitin and have become world experts in its synthesis and linkage to cancer-homing molecules. This work, widely considered a landmark synthetic achievement (nominated as one of 8 molecules of the year by the American Chemical Society) has been downloaded over 15,000 times. In the past four years we have made remarkable progress at understanding key components of the toxin's activity and controlling toxicity with compositions that enable targeting with light or exploiting lysosomal enzymes to achieve targeted applications on cells and in mice. With enhanced understanding of amanitin toxicity, we are proposing to develop more toxic amatoxins, screen them to find ones that will be less toxic to liver, and generate new "smart drugs" that allow us to use synthetic amatoxins in a combination of targeted therapeutic studies to advance preclinical lead through studies in mice. We will also explore its underlying toxicity in cells through the use and design of new amatoxins that are expected to provide cancer-specific toxicity.