The research, which appears in the March 4 issue of Nature Biotechnology, reports on collaborative work by a team of biomedical engineers and chemists at Boston University. The team was led by Tim Gardner, an assistant professor in the College of Engineering’s Department of Biomedical Engineering (BME) and its Center for BioDynamics, and James Collins, a professor in BME and co-director of the Center for BioDynamics, and done in collaboration with Scott Schaus and Sean Elliott, assistant professors in BU’s Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD).
Although drug development is an active field of research, there have been few ways to predict optimal drug design. The molecular targets of many drug candidates are unknown and are often difficult to tease out from among the thousands of gene products found in a typical organism. This “blindness?in the welter of potential cellular targets means that the process of designing therapeutic drugs is neither precise nor efficient.
The BU research team sought to bring precision and efficiency to this discovery process. The team used a combination of computational and experimental methods to build and verify their tool, first using a reverse-engineering approach to decipher the multitude of regulatory networks operating among genes in a simple organism, then testing the ability of the resulting network models to predict gene and pathway targets for a variety of drug treatments. Finally, they used the tool to predict the molecular ta rgets of a potential new anticancer compound, PTSB, shown in CMLD studies to inhibit growth in the test organism (baker’s yeast) as well as in human small lung carcinoma cells.
Their algorithm predicted, and subsequent experiments verified, that PTSB acted on thioredoxin and thioredoxin reductase, findings that not only validate the tool’s capability but could also pave the way to investigations of a potentially new class of therapeutic compounds.
In addition to Gardner, Collins, Schaus, and Elliott, the research team included Diego di Bernardo, an investigator at the Telethon Institute for Genetics and Medicine in Naples, Italy; Michael Thompson, a research associate in BU’s Center for BioDynamics; and BU students Erin Eastwood, a graduate student in chemistry, and Sarah Chobot and Andrew Wojtovich, chemistry undergraduates in the College of Arts and Sciences.
The research was supported by funds from the Department of Energy, the National Institutes of Health, the National Heart, Lung, and Blood Institute’s Proteomics Initiative, the Whitaker Foundation, the National Science Foundation, Boston University, and the Pharmaceutical Research and Manufacturers of America Foundation.