At UCSF's Small Molecule Discovery Center, researchers are always hoping to hit it big. In this case, the challenge is a rare and mysterious class of diseases, caused by misshapen proteins called prions.
"There's a not treatment for prion diseases currently and I think the reason is that it's the most recent of the diseases that's been discovered in the last couple of decades, so it's really uncharted territory," said Adam Renslo, Ph.D. from UCSF.
Prions first entered popular consciousness as the cause of mad cow disease. In humans it's known as creutzfeldt-jakob disease or CJD -- a brain disorder that triggers severe dementia, and an agonizing death. It's characterized by the presence of prions attached to neurons in the brain.
"And for that, one of the key criteria was that molecules would have to cross the blood brain barrier," said Renslo.
Renslo is associate director of chemistry at the center, located at UCSF's Mission Bay campus. His team joined forces with two other labs at UCSF, using robotic technology that can screen tens of thousands of molecules in a short period of time for their effectiveness in targeting the prions. But even with that technology, finding the right match is something like looking for a needle in a haystack.
"We looked at a particular class of neuronal cells that can be grown in a dish and can be infected with prions and then we screened a large numbers of compounds, small molecules, to see if any of those reduce the amount of prion in those cells," said Renslo.
And because CJD is a brain disease, locating possible compounds to treat it is just the beginning. Michael Silber, Ph.D., is chief of drug discovery at UCSF's Institute for Neurodegenerative Diseases.
"A drug is never going to be a hit or even a confirmed hit, because typically those compounds have not been optimized for their drug-like properties, including the ability to penetrate the blood brain barrier," said Silber.
He says chemistry teams at the small molecule center synthesize promising compounds, tweaking their properties in the process. Last month, the group announced that it had zeroed in on a specific type called aminothiazoles. After confirming their modified compounds were able to cross into the brain, they began testing them in mice infected with prion disease.
"We can extend survival of mice that would normal die in 110 days with this disease. They can live to as much as 250 days," said Silber.
In effect, that is more than doubling their life expectancy. He says it will likely be several years before a drug would be ready for human trials, but he's confident they're on the trail of cracking this mysterious and deadly disease.
The UCSF research team also includes Stanley Prusiner, M.D., who was awarded the Nobel Prize in 1997 for discovering prions and suggesting that they might be linked to CJD and mad cow disease.
Written and produced by Tim Didion