Chemical Pass Escorts Drugs Inside Cells

SAN FRANCISCO--For pharmaceutical-makers, discovering a new drug isn't the whole battle. Getting a compound inside cells can be just as difficult. Water-soluble drugs, for example, can move through the bloodstream, yet once they arrive at their destination, they're stopped by the fatty membrane surrounding cells. Now researchers have found a chemical tag that appears to act as a universal pass, escorting compounds inside cells.

Discovery of the new all-purpose pass, a peptide, or short fragment of protein, was inspired in part by a surprising source: the AIDS virus. In the early 1980s, researchers discovered that a protein fragment called Tat helps HIV viral proteins enter cells. Other research teams showed that linking Tat to drugs can help boost their uptake. But Tat is hard to synthesize and too expensive for widespread use, so a team led by organic chemist Paul Wender of Stanford University set out to find a cheaper, more effective alternative.

The researchers started by analyzing Tat and then systematically rearranging its amino acids. After testing many candidates, they found one version--a chain of arginines--that was even more effective than Tat at infiltrating cells. When they tested the peptide, it ferried a drug right through human skin grafted onto a mouse--an impossible feat without the peptide, they reported last week at a meeting of the American Chemical Society.

"This is an important development," says John Voorhees, a dermatologist at the University of Michigan Medical School in Ann Arbor. When physicians treat skin conditions, they give a drug in capsule form and hope that some of it will make its way from the gut to the bloodstream and eventually inside skin cells. A topical cream could be more effective for treating conditions such as psoriasis and eczema and might carry fewer side effects, Voorhees says.