David M. Perrin
University of British Columbia
Talk Session: SESSION 7: PEPTIDES IN DELIVERY
Date: Monday, June 13, 2022
Talk Time: 04:50 pm - 05:10 pm
Talk Title: Improving on Alpha-Amanitin, one of Nature's Most Toxic Peptides - Synthesis of More Cytotoxic Analogs, Bioconjugation and Use in Peptide-Directed Targeted Therapy
David M. Perrin holds the rank of Full Professor and has authored over 100 publications. Professor Perrin’s work amalgamates synthetic organic chemistry, molecular biology, physical organic chemistry and radiochemistry to address long-standing challenges at the interface of chemistry and biology where research outputs have had major impacts at a fundamental level as well as in several therapeutic applications, a theme that now unites his work.
Professor Perrin has received numerous competitively reviewed grants, CIHR operating grants, an NSERC accelerator grant, Junior- and Senior-scholar awards of the MSFHR, three Innovation Grants from the CCRSI, a New Directions grant from the Petroleum Research Fund, and a MSFHR Innovation-to-Commercialization grant, is an inventor on 5 patents, granted or pending, was awarded the Teva and Belleau Awards of the Can. Chem. Soc., is a co-founder of Alpha9Theranostics Inc., and is proud to have mentored postdoctoral fellows, graduates and undergraduates, many of whom now hold positions in academia and industry.
Professor Perrin has established himself as a leading researcher in bio-organic chemistry. Specifically, Dr. Perrin has generated creative solutions and gained new insights to the following long-standing problems in chemical biology: 1: synthesis of RNaseA mimics for destroying pathogenic mRNAs and selection of modified DNA aptamers for target recognition and sensing, 2: a chemical platform for one-step 18F-radiolabeling based on novel applications of boron-based chemistry for PET imaging cancer, 3: the synthesis of peptide natural products, notably alpha-amanitin; 4: Synthesis of novel heterocycles for the rationally designed recognition of DNA. Each project has generated a sustained publication record in high-impact, peer-reviewed journals and reflects a high degree of chemical/biological novelty, scientific rigor and long-term direction towards translational potential.
Alpha-amanitin is a classic natural product that was isolated 80 years ago from the notorious death-cap mushroom, Amanita phalloides. Alpha- amanitin is a potent, orally available, highly selective allosteric inhibitor of RNA polymerase II, Pol II, now features as a highly toxic payload for antibody-drug conjugates. Our first total synthesis of amanitin in 2018 has empowered access to new analogs that are more cytotoxic than the natural product.
These analogs present discrete modifications to the polypeptide backbone as well as adjustments in "chi" space to rigidify the toxin. Nevertheless, the full basis for their enhanced cytotoxicity is not correlated with in vitro inhibitory activity of Pol II catalyzed transcription. To begin to address, we have developed the first photo-activatable amanitin whereby light is used to initiate cell death.
Finally, we have designed a series of modularly "clickable" linkers by which entirely synthetic toxins are conjugated to octreotate; these show low nanomolar cytotoxicity on Ar42J cells and promising in vivo targeting applications in mice.