More MS news articles for Sep 2001

Feverfew's Mechanism of Action Suggests New Class of Anti-Inflammatories

http://www.medscape.com/reuters/prof/2001/09/09.14/20010913drgd001.html

WESTPORT, CT (Reuters Health) Sept 13 - The active ingredient in the medicinal herb feverfew, parthenolide, targets a catalytic subunit of the I-kappa-B kinase (IKK) complex, which stimulates genes involved in inflammation, researchers at Yale University report. Identifying the mechanism of action of this compound opens the door for the development of a new class of anti-inflammatory agents.

Feverfew has been used for centuries as a remedy for migraine headaches and fever, Dr. Craig M. Crews noted in an interview with Reuters Health.

He and associates in New Haven, Connecticut report in the August issue of Chemistry and Biology that parthenolide specifically binds to and inhibits IKK-beta, which plays a critical role in cytokine-mediated signaling. The researchers showed that the covalent interaction between parthenolide and IKK-beta is specific and saturable, and that it is independent of upstream kinases.

The researchers went so far as to determine that substitution of a single amino acid, cysteine 179, renders IKK-beta insensitive to parthenolide. "Given the lack of parthenolide sensitivity in the C179A mutant, this cysteine residue is a likely candidate for the site of covalent modification by parthenolide," they write.

In the interview with Reuters Health, Dr. Crews pointed out that "the target IKK-beta has been identified only within the last few years." The pharmaceutical industry has conducted "massive research" for compounds that will target the IKK pathway, he said, but has reached a bottleneck.

"Now that we know the genetic profile of humans, drug companies are realizing they can't make a drug against every single gene product," Dr. Crews explained. "So the question is, how do they focus their efforts?"

He suggests that, as in this study, researchers should start with compounds that they know are active. "They are inherently validated as drug targets if the receptors are identified," he added.

"By understanding how they work at the molecular level, that information can be valuable in developing drugs that don't have the undesirable side effects that the original natural product has," Dr. Crews said. "Why challenge your liver to remove all the extra toxins?"

Dr. Frederick Freitag, of Diamond Headache Center in Chicago, commented on the findings, telling Reuters Health, "Some patients report that feverfew is helpful for their headaches. The biggest problem is its relative impurity. It's hard getting good quality preparations."

"A lot of these compounds have a lot of potential promise for patients," Dr. Freitag added, "but they have to be constructed properly."

Chem Biol 2001;114:1-8.
 

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