Unlocking the secrets of aspirin

USA Today (Society for the Advancement of Education), Feb, 1996

Aspirin is nearly 100 years old, and its forerunner - willow bark - was used for many centuries. Only recently, though, did scientists discover the target of these drugs, and researchers at the University of Chicago Medical Center have unearthed the precise chemical mechanism of how aspirin stops pain and inflammation. The finding means that millions of arthritis sufferers and others who regularly take aspirin to reduce pain and inflammation may be able to look forward to improved drugs with fewer side effects.

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and indomethacin work by inhibiting an enzyme which produces prostaglandins - hormone-like messenger molecules that trigger many processes in the body, including inflammation. The researchers have shown that aspirin splits into two parts and affixes one part to the enzyme, permanently altering its chemical structure and blocking the reaction that produces prostaglandins. Aspirin is the only NSAID known to work in this manner.

Led by Michael Garavito, associate professor of biochemistry and molecular biology, they determined the molecular structure of the enzyme, prostaglandin H2 synthase, or PGHS. Using X-rays to probe the positions of atoms in tiny crystals of the enzyme, they showed that PGHS has tunnel running into the middle of it. The raw material must pass through this tunnel to reach the core of the enzyme, where it will be converted into prostaglandin.

Aspirin, permanently attaches a portion of itself inside the tunnel, where it acts like a gate, blocking prostaglandin's precursor from reaching the "active site" of the enzyme. This gate can be in two positions, either fully or partially closed, and the position of the gate may differ between two forms of the enzyme found in the body. Finding such differences between the two forms is the key to developing improved NSAIDs.

In 1991, several groups found that the body has two types of prostaglandin H2 synthase: an ever-ready PGHS-1, present in nearly all cells for basic house-keeping duties, and PGHS-2, made only as needed and just by those cells involved in inflammation and immune responses. Unfortunately for pain sufferers - and especially for rheumatoid arthritis patients, who must take huge doses daily - none of the current crop of 16 NSAIDs discriminates between the two enzyme forms. Before it can trickle into the bloodstream and alleviate inflammation by reining in PGHS-2, the drug lands with a thud in the stomach, where it knocks out PGHS-1, causing excess acid secretion and stomach upset or ulcers.

"... The consensus in the pharmaceutical community was you couldn't build a better aspirin," Garavito points out. "But understanding the differences between the two forms of PGHS may allow us to do exactly that. We know that PGHS-2 is only partly blocked by aspirin, while PGHS-1 is completely blocked out.... The bottom line is that, although the two forms of the enzyme seem very similar, their active sites are subtly different, and this could be a basis for rational drug design."

Drug developers are most interested in targeting PGHS-2, and Garavito's laboratory s trying to grow crystals of that form of the enzyme large enough to X-ray. However, aspirin's beneficial effects in preventing vascular disease and heart attacks are thought to be a PGHS-1 phenomenon, and improved anti-platelet drugs may derive directly from the study.