New approach offers drug-discovery shortcut
action without the need for an appropriate molecular target has
been used to suppress genetic mutation. The discovery raises new
hopes of identifying potential new drugs, harnessing this new
drug-discovery approach to other diseases.
The research, published in the May issue of Nature Biotechnology, focused on the chemical suppression of a genetic mutation in a zebrafish model of aortic coarction. What was unique in their research was they did not identify a molecular target for the new drug - a factor that is paramount in current procedures.
Randall Peterson of the MGH Cardiovascular Research Centre (CVRC) said: "Currently most drugs are designed to act on a specific protein, but for most diseases we still don't know what the protein targets should be."
"This is a totally different approach that shows how, without knowing the best target, you can screen for drugs that could reverse a disease and in the process learn something new about the underlying biology."
Conventional drug discovery approaches require a specific selection of an appropriate molecular target, but it is not often obvious which biological pathways must be targeted to reverse a disease genotype.
However, phenotype-based screens offer the potential to identify pathways and potential therapies that influence the disease processes.
The researchers used Zebrafish embryos - a tiny tropical fish used as a model of vertebrate development. They are vulnerable to a mutation known as gridlock. Here the mutation disrupts aortic blood flow in the lower region in a physiological manner similar to aortic coarctation in humans.
Researchers exposed the embryos to 5000 types of small molecules to see if any would prevent expression of the gridlock mutation. It was found one molecule, GS4012, appeared the most effective. Further experiments showed that GS4012 appears to promote the activity of the vascular endothelial growth factor (VEGF) and also induces the development of vascular networks in cultured human vascular cells.
While this molecule may eventually have clinical application in promoting vascular growth after heart attack, stroke or injury, this new way of identifying potential new drugs is set to have a wider impact.
Peterson said: "We were able to find a compound that could reverse the mutation and are hopeful that it will provide fundamental new insights into vascular development and disease."
In further studying the mechanism behind the action of the gridlock suppressors identified, the research team hope to apply this new drug-discovery approach to other diseases.
