There are two forms of cyclooxygenase: COX-1, present all the time in the stomach, whose prostaglandin products are responsible for protecting the stomach lining from irritation; and COX-2, produced in response to stimuli, whose prostaglandin products result in pain and inflammation.
Aspirin and non-steroidal inflammatory drugs (NSAIDs) target both enzymes, resulting in relief from pain and inflammation but also causing stomach upset and even ulcers. Recently developed drugs like celecoxib target only COX-2 but leave COX-1 alone, providing relief with fewer gastric side effects. They are also being tested for their potential to prevent colorectal cancer.
These drugs bind at the same site on COX-2 where the arachidonic acid is bound in the snapshot, Marnett said, although they do not fit the "pocket" in precisely the same way.
Marnett and his colleagues have developed another COX-2 selective molecule, called APHS, that differs from other COX-2 inhibitors in that it permanently inactivates COX-2 like aspirin does. The other COX-2 inhibitors and NSAIDs only temporarily block its action. Marnett noted that their research suggests APHS binds instead in the same pocket where prostaglandin PG2 was attached to COX-2. "So there's something inside that pocket that appears to be important for the COX-2 selectivity of APHS," Marnett said.
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Contact: Cynthia Manley
cynthia.manley@mcmail.vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
3-May-2000