April 23, 2004

New approach offers potential drug-discovery shortcut

Researchers from the MGH Cardiovascular Research Center (CVRC) have developed a way of identifying promising new drugs that may get around a major challenge in drug discovery. In the May issue of Nature Biotechnology the team describes using an animal model to screen for a compound that suppresses a serious genetic mutation without first identifying a molecular target for the new drug, something that is a key bottleneck in current procedures.

"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," says Randall Peterson, PhD, of the CVRC, the paper's lead author.

The researchers started with embryos of zebrafish with a mutation called gridlock, which prevents the correct development of the circulatory system in the lower portion of the body. By exposing a panel of these embryos to a library of 5,000 small molecules, they identified two that prevented expression of the gridlock mutation. Further study with the most powerful of these compounds indicated that it was most effective at a developmental stage right before and during the formation of major vascular structures and promotes the activity of a key angiogenesis factor.

"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 may have an even greater impact," Peterson says. The paper's senior author is Mark Fishman, MD, formerly director of the CVRC and chief of MGH Cardiology, now president of the Novartis Institutes for BioMedical Research. Co-authors include Stanley Shaw, MD, PhD, Travis Peterson, David Milan, MD, and Calum MacRae, MBChB, all of the CVRC.