Designer molecules that combine metals such as copper with natural organic materials could treat diseases in the body

Aug 30 2005

Designer molecules that combine metals such as copper with natural organic materials could one day attack viruses in the body and treat a wide range of diseases.

That's the finding of chemists at Ohio State University, who have successfully tested such molecules against portions of HIV and Hepatitis C virus RNA in the laboratory. They've also created molecules that act like ACE, or angiotensin-converting enzyme, inhibitors - drugs that are used to lower blood pressure.

At the American Chemical Society national meeting in Washington, DC, project leader James Cowan described how the same patent-pending technology could one day produce novel anti-tumor agents.

Drugs based on these molecules could produce fewer side effects compared to some of today's treatments, and they could also combat drug resistance, said Cowan, professor of chemistry at Ohio State.

Pharmaceutical companies tend to make drugs from the same limited set of ingredients, drawing upon only about a half-dozen of the more than 100 known chemical elements, Cowan explained. At the same time, drug-resistant bacteria and viruses are emerging.

"Faced with a problem like that, you can't ignore 95 percent of the periodic table," he said. "We have to start broadening the landscape of drug design."

His new molecules, called metal coordination complexes, mimic the activity of natural enzymes that break apart DNA, RNA, and proteins in the body.

Cowan and his colleagues have tailor-made different complexes to break apart portions of RNA that enable HIV and Hepatitis C viruses to function, as well as the ACE enzyme that constricts blood vessels in the body. In test tubes and in cell cultures of E. coli, the complexes targeted these particular RNA structures and enzymes and destroyed them.

The complexes work in one of two ways. Some use a process called redox chemistry to steal electrons from the bonds holding the target molecule together. Others use hydrolysis, meaning that they break down the target's chemical waterproofing, so that the water that is naturally present in a cell dissolves the target.

That's what makes these complexes different from most drugs.

"Most drugs are designed to inhibit - that is, they will bind to a protein molecule and just block its function," Cowan said. "But with metals you have the option of completely destroying the target."

He hopes that with proper tailoring to certain metabolic enzymes, these strategies could work against cancer. He also sees applications in homeland security, such as complexes that destroy the anthrax bacterium.

Even though these new complexes are partly made of metal, drugs based on them could potentially be less toxic to the body than conventional treatments.

Metals can be toxic, but so can some organic molecules that are used as drugs, Cowan pointed out.

One of these complexes could destroy a target, and then move on to another, eventually destroying many targets. So a smaller dose of a metal complex could do the work of a larger dose of a traditional drug.

Completely destroying the target molecule also lowers the chance that a virus will develop a drug-resistant strain.

The chemists are also working on metal-free versions of their molecules that will assemble themselves on site, by harvesting the metal that is naturally present in cells. It's a matter of designing an organic molecule that will have a natural affinity for the small amounts of iron or copper that are already inside the body - one that will then target the right viral RNA once it's assembled.

One of the potential obstacles to using metals as drugs is that the Food and Drug Administration doesn't yet have streamlined procedures for approving the compounds. But Cowan is confident that the situation will soon change, given the need for alternatives to traditional drugs.

He feels that these metal complexes represent a good first step toward the development of multi-functional drugs called dual-activity agents.

"What the industry really needs for the next generation are compounds that work on more than one target, because this will really accelerate progress against disease," he said.

He offered heart disease as an example. Today, people often must take several drugs to combat different cardiovascular enzymes. One dual-activity drug could do the work of two, by lowering blood pressure and simultaneously reducing the formation of arterial plaque.