A molecule designed to mimic an enzyme can fight highly reactive molecules that contribute to arthritis and other inflammatory conditions, according to a report in today's Science.
The body protects itself against corrosive superoxide radicals by deploying superoxide dismutases (SODs), a family of enzymes that defang superoxide by transforming it into molecular oxygen and hydrogen peroxide. Indeed, SODs themselves once looked like promising candidates to treat inflammatory conditions such as rheumatoid arthritis. But they have been shown to trigger adverse immune reactions in some patients; in addition, like other proteins, native SODs are rapidly broken down by the body's many protein-destroying enzymes.
To come up with an alternative compound, a team led by pharmacologist Daniela Salvemini and chemist Dennis Riley of MetaPhore Pharmaceuticals in St. Louis started with manganese, the least toxic of the three metals that can duplicate SOD's catalytic activity. By trial and error, the researchers produced a ring structure that holds onto manganese reasonably well. Then, by computer modeling and with many animal tests, they developed a derivative that was even more stable and more effective in breaking down superoxide.
This compound, known as M40403, transforms superoxide at rates similar to those of native SOD and does not break down in the body. When injected into rats, M40403 greatly decreased several key indicators of inflammation such as swelling, tissue damage, and white blood cell accumulation at an injury site. In another series of animal tests, M40403 reduced the "reperfusion" injury that occurs when clot-busting drugs are used to treat a heart attack or stroke.
M40403 is not the first nonprotein SOD mimic researchers have identified, but it is more specific in its action than the others. "They've taken a prototype drug and shown that it has therapeutic activity in animals," says John Groves, a chemist at Princeton University. Salvemini says the team hopes to conduct safety studies then determine whether the compound has therapeutic value in people.