“We identified and isolated in sea sponges a compound called latonduine and developed a method to determine its site of action,” said Prof. David Thomas, Chair of McGill’s Dept. of Biochemistry and Canada Research Chair in Molecular Genetics. The team examined 720 marine extracts from South Pacific sponges to identify latonduine as the active molecule.
The researchers built upon their ongoing research, which centers on treating the most common mutant form of the cystic fibrosis transmembrane conductance regulator (CFTR) to correct the basic defect that causes most CF cases. This membrane protein is involved in ion and water transport across cells that line the airways and other organs. In people with CF, the mutant protein does not fold correctly and is retained within the cell instead of reaching its normal location at the cell surface. CF results from this failure to localize correctly in the cell.
This new compound, which had no previous known biological function, becomes a novel candidate for further CF research. “In the past, people have looked under the streetlight for lost keys, but we choose to search for our keys using a flashlight in other untapped areas,” said Graeme Carlile, a McGill research associate and co-author.
The breakthrough is the result of a continuing collaboration between the groups of Prof. Raymond Andersen at UBC, Prof. John Hanrahan, from McGill’s Department of Physiology and Prof. Thomas. Prof. Andersen is a natural products chemist who specializes in isolating novel molecules from marine sponges. His group has identified many biologically active compounds from this unique source.
Now that lantonduines have been shown to correct the most common CFTR mutant, work can begin on identifying the critical pathways that mediate this correction with a view to advancing treatment of CF.
“As a disease with roughly 80,000 patients world-wide, CF has not been a priority for major pharmaceutical companies, although this is changing with the recent approval of a drug for treating a less common CFTR mutant. The search for a cure by our team is an ambitious project which harnesses the expertise and commitment of McGill and UBC researchers in chemistry, physiology and molecular biology. While we are making progress, we will require more resources and wider expertise,” said Prof. Thomas.
This work is funded by grants from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, Cystic Fibrosis Canada, the Canada Foundation for Innovation, and the Canada Research Chairs program.