Sneaking drugs past the brain's barrier.

By incorporating a protein into a fatty molecule, pharmacologists can disguise the protein well enough to slip it through the specialized brain-protecting structure called the blood-brain barrier, which normally excludes proteins.

This strategy may offer a new means of sneaking drugs for chronic pain and other central nervous system disorders past the brain's sentry.

Nicholas Bodor and his colleagues at the University of Florida in Gainesville sandwiched a naturally occurring pain-relief protein called enkephalin between a fatty acid and a molecule that becomes positively charged in the presence of enzymes found in the brain. The researchers report in the Sept. 18 SCIENCE that the fatty acid enabled the hybrid molecule to pass through the oily blood-brain barrier. Moreover, Bodor's team found that when the molecule became positively charged on the other side of the barrier, the change prevented it from diffusing back out into the bloodstream.

Using a sensitive technique called mass spectrometry, the Florida researchers determined that once the hybrid enkephalin molecule was trapped in the brain, other brain enzymes stripped off its disguise, freeing the drug to perform its pain-relieving role. They proved this by showing that injections of the intact hybrid enkephalin molecule prevented a group of rats from reacting as strongly to a mildly painful stimulus as a second group given an inactive control compound.

Bodor's group projects that the strategy will yield "a future generation of high-efficiency neuropharmaceuticals." Next, they plan to design hybrid molecules that will not only ferry protein drugs across the blood-brain barrier, but also regulate the release of the drugs once in the brain.