Washington, DC – Designer molecules that combine metals suchas copper with natural organic materials could one day attack virusesin the body and treat a wide range of diseases.
That's thefinding of chemists at Ohio State University, who have successfullytested such molecules against portions of HIV and Hepatitis C virus RNAin the laboratory. They've also created molecules that act like ACE, orangiotensin-converting enzyme, inhibitors – drugs that are used tolower blood pressure.
At the American Chemical Society nationalmeeting in Washington, DC, project leader James Cowan described how thesame patent-pending technology could one day produce novel anti-tumoragents.
Drugs based on these molecules could produce fewer sideeffects compared to some of today's treatments, and they could alsocombat drug resistance, said Cowan, professor of chemistry at OhioState.
Pharmaceutical companies tend to make drugs from the samelimited set of ingredients, drawing upon only about a half-dozen of themore than 100 known chemical elements, Cowan explained. At the sametime, drug-resistant bacteria and viruses are emerging.
“Facedwith a problem like that, you can't ignore 95 percent of the periodictable,” he said. “We have to start broadening the landscape of drugdesign.”
His new molecules, called metal coordination complexes,mimic the activity of natural enzymes that break apart DNA, RNA, andproteins in the body.
Cowan and his colleagues have tailor-madedifferent complexes to break apart portions of RNA that enable HIV andHepatitis C viruses to function, as well as the ACE enzyme thatconstricts blood vessels in the body. In test tubes and in cellcultures of E. coli, the complexes targeted these particular RNAstructures and enzymes and destroyed them.
The complexes work inone of two ways. Some use a process called redox chemistry to stealelectrons from the bonds holding the target molecule together. Othersuse hydrolysis, meaning that they break down the target's chemicalwaterproofing, so that the water that is naturally present in a celldissolves the target.
That's what makes these complexes different from most drugs.
“Mostdrugs are designed to inhibit – that is, they will bind to a proteinmolecule and just block its function,” Cowan said. “But with metals youhave the option of completely destroying the target.”
He hopesthat with proper tailoring to certain metabolic enzymes, thesestrategies could work against cancer. He also sees applications inhomeland security, such as complexes that destroy the anthrax bacterium.
Eventhough these new complexes are partly made of metal, drugs based onthem could potentially be less toxic to the body than conventionaltreatments.
Metals can be toxic, but so can some organic molecules that are used as drugs, Cowan pointed out.
Oneof these complexes could destroy a target, and then move on to another,eventually destroying many targets. So a smaller dose of a metalcomplex 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.
Thechemists are also working on metal-free versions of their moleculesthat will assemble themselves on site, by harvesting the metal that isnaturally present in cells. It's a matter of designing an organicmolecule that will have a natural affinity for the small amounts ofiron or copper that are already inside the body – one that will thentarget the right viral RNA once it's assembled.
One of thepotential obstacles to using metals as drugs is that the Food and DrugAdministration doesn't yet have streamlined procedures for approvingthe compounds. But Cowan is confident that the situation will soonchange, given the need for alternatives to traditional drugs.
Hefeels that these metal complexes represent a good first step toward thedevelopment of multi-functional drugs called dual-activity agents.
“Whatthe industry really needs for the next generation are compounds thatwork on more than one target, because this will really accelerateprogress against disease,” he said.
He offered heart disease asan example. Today, people often must take several drugs to combatdifferent cardiovascular enzymes. One dual-activity drug could do thework of two, by lowering blood pressure and simultaneously reducing theformation of arterial plaque.
This work was funded by the National Institutes of Health.
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