Contents
- Funding Matters
From Brain Imaging to Chemical Probes
Funding Matters
From Brain Imaging to Chemical Probes
Grants enable advanced technologies.
Pellecchia’s NMR instrument is also having a far-reaching impact on the work of researchers throughout the country. His group has pioneered using information collected by NMR spectroscopy to design small molecules, called chemical probes, to disrupt interactions among proteins. Doing so may reveal the importance of a particular interaction or pathway to disease and also give researchers a starting point for drug development.
Pellecchia and colleagues recently used the technique to identify chemical probes for the protein Bid, a molecule that causes neuronal cell death and is a suspected player in brain injury and neurological disorders, such as amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease.
Scientists at the Burnham Institute for Medical Research in La Jolla, Calif., are using nuclear magnetic resonance spectroscopy to probe interactions between small molecules and proteins as a first step in identifying potential drug targets. New instruments, supported by an NCRR High-End Instrumentation grant, will allow more researchers to benefit from the technology. (Image courtesy of Burnham Institute for Medical Research)
Traditional drug discovery techniques often look for “downstream” targets of a protein—for example, in the case of an enzyme, the molecules the enzyme modifies. But because Bid is not an enzyme, it is not easily amenable to such approaches. Pellecchia used NMR spectroscopy to understand the structure of Bid and, in particular, the part of the protein that interacts with other molecules. He then used this information to design several chemical probes that stick to Bid, preventing it from finding its “partners.” By preventing these interactions from occurring, the chemical probes also prevented Bid from inducing neuronal cell death. After further optimization, these chemical probes will be tested in animal models for their potential use in preventing nerve cell damage due to brain injury and other conditions.
One of the limitations of using NMR spectroscopy is that typically the technique can be used on only one sample at a time. In addition, the amount of sample needed for a single experiment can be substantial, depending on the instrument’s signal-to-noise ratio, or its ability to distinguish a true signal from background noise. With the $1.45 million HEI grant, Pellecchia was able to purchase a 700-MHz NMR instrument with an accessory that generates a substantially higher signal-to-noise ratio, reducing the amount of sample needed for a study. The new instrument also comes with an automated sample changer, allowing it to test multiple samples automatically, greatly increasing the speed and efficiency of experiments.
The new NMR instrument will support several multidisciplinary projects by Burnham Institute investigators focused on infectious diseases and signal transduction in cancer cells. It also will serve, in part, the San Diego Center for Chemical Genomics, as part of an NIH Roadmap Network to accelerate medical discoveries. All NIH-funded researchers can collaborate with members of the Network to identify small molecules that act in their favorite pathway. As Pellecchia points out, the San Diego Center for Chemical Genomics is the only center in the Network that will use NMR spectroscopy. “We are proud of that fact,” he says. “And we are thrilled we’ve been awarded an additional instrument to support research in this area.”
—Frances McFarland Horne
