at the University of Toronto
OUR CURRENT RESEARCH PROJECTS
PEXIL™ TECHNOLOGY
The world is in desperate need of new drugs to combat drug-resistant pathogens, parasites and crop pests. To help accelerate drug discovery, Peter’s group has recently developed a new, high-throughput, massively paralleled drug/pesticide screening technology called PEXIL™. PEXIL’s advantages over traditional phenotypic screens using single pathogens or agricultural pests include: i) targeting of 100s of pathogens or pests simultaneously; ii) the delivery of new targets that enable medicinal chemistry optimization of new small molecule leads, and, iii) the ability to target pathogens and pests that are simply unscreenable in high-throughput fashion (i.e. schistosomes, cestodes, insects, plant parasitic nematodes etc).
ANTIPARASITIC PRODRUGS
Parasitic nematodes are estimated to destroy over $150B USD worth of crop every year. Towards developing nematicides to improve global food security, the Roy Lab has discovered a suite of small molecule scaffolds that are active against plant parasitic nematodes. These molecules are bioconverted within nematodes into lethal products. The bioconversion of one of these scaffolds, which they call Selectivin™, is restricted to nematodes. The Roy Lab uncovered the details of how Selectivin™ works and show demonstrable utility against some of the world’s most destructive plant parasitic nematodes in green house-based assays.
NOVEL NEUROMODULATORY NEMATICIDES
The Roy Lab has developed a drug-screening pipeline that reveals small molecule disruptors of motor behaviour in nematodes. Nementin™ is one scaffold revealed by this screen. Nementin™ induces convulsions, paralysis and death though massive neurotransmitter release. Nementin™ also dramatically enhances the activity of organophosphate and carbamate pesticides that are used kill nematodes. Hence, Nementin™ may have utility in reducing the amount of these non-specific pesticides that are used in agriculture.
LIVER DISEASE
PFIC3 is a rare liver disease that manifests in early childhood and often requires liver transplantation. The disease is caused by defects in the liver’s ABCB4 lipid pump. By knocking out an ABCB4 homolog in the worm, Peter’s lab has established a new PFIC3 nematode model. They used this model to identify 30 FDA-approved compounds that suppress the worm’s defects associated with loss of the presumptive lipid pump. Exploiting C. elegans forward genetic screens, the group showed that these FDA compounds likely upregulate alternative pumps to make up for the loss of the ABCB4 homolog. Together with collaborators, Peter’s group is testing whether these FDA compounds can successfully treat a mouse model of PFIC3.
AMYLOID DISRUPTORS
Over 50 human diseases are thought to have amyloid formation as their root cause. These include Parkinson’s, ALS, scrapie, Huntington’s, and perhaps Alzheimer’s to name but a few. The Roy Lab has previously found that select small molecules crystalize in association with the nematode’s pharynx cuticle (see their Kamal et al., 2019 paper for details). Peter’s group recently made the fortuitous discovery that molecules known to disrupt amyloid formation suppress crystal formation. Hence, screens for molecules that disrupt crystal formation may yield novel amyloid-busters.