New 'antisense' Complexes Pack Catalytic Punch, UB Team Reports

WASHINGTON, D.C. -- New metal complexes that stay intact while catalytically destroying ribonucleic acid (RNA) have been synthesized by University at Buffalo researchers.

The complexes hold promise for the development of new "antisense" drugs to prevent expression of specific proteins critical to the replication of viral or cancer cells by attacking a specific portion of their RNA.

The work was reported today (Thursday, Aug. 25) at a meeting of the American Chemical Society in the Renaissance Hotel.

"Once a piece of RNA is cleaved, it can't be translated into a viral protein or an oncogene product," said Janet R. Morrow, Ph.D., UB assistant professor of chemistry and principal investigator. "If we can selectively inhibit the expression of a particular gene by destroying messenger-RNA, then it could be possible to develop a specific antiviral or anticancer agent."

The UB researchers' approach, on which patents have been filed, combines lanthanide-based metal complexes, which catalytically destroy RNA, with "antisense"molecules, a fragment of DNA whose base sequence is arranged in a specific order to recognize a targeted strand of RNA.

A key advantage to the complexes is that while they act catalytically, they never release their metal ion, a recurring problem with metal complexes.

Morrow explained that this is because the metal ion is connected to a preorganized ligand, a molecule specifically designed to bind to the metal.

When the metal promotes the RNA cleavage, the RNA backbone undergoes transesterification, a desirable type of reaction because it produces a "clean break" in the RNA.

"With other types of reactions, you can end up destroying other proteins that are important, or you can end up destroying the catalyst itself," said Morrow.

The UB group is one of a handful in the U.S. using lanthanide complexes to construct "antisense" molecules.

"It's very difficult to design metal complexes that stay intact in physiological conditions, but which will still perform catalysis," said Morrow. "Our lanthanide complexes do both."

The UB researchers are conducting joint research on the complexes with Isis Pharmaceuticals of San Diego.