Nanotech tool aids drug discovery
“The nice thing about this technology is you don’t have to gain access to the inside of a cell, or put a foreign reporter molecule into the cell, which can change its characteristics. This can all be accomplished from the outside, using very natural activation patterns.”
Robert A. Pearce
Professor of Anesthesiology
Identifying promising new agents to treat disease is a high-stakes roll of the dice for biomedical science. To find effective and safe medicines, an array of sophisticated and expensive drug-discovery schemes are deployed to ferret out promising new compounds.
Now, with support from the Discovery Seed Grant Program, Wisconsin scientists are poised to bring a novel approach to finding new medicines by deploying the atomic force microscope — the foremost tool of the nanotechnologist — to screen agents as they dock with critical cell receptors.
The effort, led by Robert A. Pearce, professor of anesthesiology in the School of Medicine and Public Health, is aimed squarely at developing a high-throughput drug screen capable of detecting changes in the activity of receptors that control ion channels that act as a portals to the cell.
“This is the primary means of rapid signaling between cells,” explains Pearce of the ion channel proteins that let ions pass through the cell’s membrane. “It’s how they get information.”
It is through receptors and ion channels that many drugs do their work. Thus, the ability to observe the detailed interplay of a drug molecule as it interacts with key receptors can tell scientists much about how well or poorly a particular agent may fare when deployed in the body.
The Team
Principal Investigator
- Robert Pearce, Anesthesiology
Investigators
- Robert Blick, Electrical and Computer Engineering
- Cynthia Czajkowski, Physiology
- Max Lagally, Materials Science and Engineering
- Sandro Mecozzi, Pharmacy
- David Schwartz, Chemistry
- Justin Williams, Biomedical Engineering
How it works
Toward that end, Pearce and his colleagues seek to harness the atomic force microscope, a device that can image, measure and manipulate matter at the scale of atoms. It does this through the use of a probe — a very sharp tip positioned on a flexible cantilever. When the vibrating tip of the probe senses the atoms of a sample, ephemeral chemical bonds are formed, which alter the probe’s vibration and allow for detection and mapping of the sample.
By coating the tip of the probe with molecules that interact with receptors, it’s possible to detect changes in channel activity produced by a series of compounds being considered as potential drugs. That information will give scientists a sense of how they might fare as medicines.
“We’ll create a functionalized tip,” says Pearce. “In tapping mode, this will tell us about the nature of the interaction. The nice thing about this technology is you don’t have to gain access to the inside of a cell, or put a foreign reporter molecule into the cell, which can change its characteristics. This can all be accomplished from the outside, using very natural activation patterns.”
What’s more, the atomic force microscope can make these measurements at lightning speed and in rapid sequence, providing a platform for testing many compounds in a short period of time.
“In order to mimic what goes on in the brain or in muscles, you have to measure things really fast,” Pearce notes. “These interactions are hard to study, but I’m pretty optimistic that this is going to work. It’s a straightforward concept.”
Co-principal investigators for the study include pharmacy professor Sandro Mecozzi, materials science and engineering professor Max Lagally, biomedical engineering professor Justin Williams, electrical and computer engineering professor Robert Blick, and physiology professor Cynthia Czajkowski. Collaborating is genetics and chemistry professor David Schwartz.