Entering a foreign country often requires both a passport and a visa valid for that country. Now scientists have figured out a way to issue a kind of molecular visa to drugs, allowing them to pass freely through cell membranes. The findings, reported in this month's Nature Biotechnology, may allow researchers to design drugs that precisely target certain genes to treat maladies ranging from irritable bowel disease to blindness in AIDS patients.
Small DNA-like molecules, called peptide nucleic acids (PNAs), can shut down specific genes in cultured cells because their nucleic acid sequence binds tightly to complementary target DNA or RNA sequences, preventing the cell from translating a gene's code into a working protein. But it's hard in cell culture--and even harder in the body--to smuggle bulky PNAs across cell membranes.
Neurobiologist Ulo Langel of Stockholm University in Sweden, with colleagues at several other labs, solved this problem by pairing PNAs with fragments from two other proteins--transportan or pAntp--that use an unidentified mechanism to slip easily into cells. The transport proteins give the PNAs carte blanche to enter the cell membrane. The researchers attached these entry keys to PNAs designed to shut down expression of a test gene--the galanin receptor gene, which binds a protein, galanin, that helps regulate everything from pain perception to food intake.
They tested the ability of the portable PNAs to counteract galanin's pain-relieving function in rats. They gave the animals slight electrical shocks that triggered a specific pain response--a leg twitch. A dose of galanin normally could stop the leg twitching. But in rats infused with the PNA, galanin's pain-quenching ability was reduced 100-fold.
"It's great that they show that it works not merely in cells, but in animals," says microbiologist Eric Wickstrom of Thomas Jefferson University in Philadelphia. "This establishes the proof-of-principle that PNAs may be used for therapy."