"We have met the enemy, and he is us."When Walt Kelly's Pogo spoke these memorable words a quarter-century ago, he might almost have been thinking interleukin-1.This cytokine, when over-secreted by certain white blood cells, is aprime perpetrator of the immune system's inflammatory response. Thismeans it's got a heavy share in causing such autoimmune diseases asrheumatoid arthritis, inflammatory bowel disease and psoriasis. Recentfindings also indict inflammation in neurodegenerative disorders, suchas Alzheimer's and Parkinson's diseases.Aspirin _ salicylic acid _- has been the drug of choice in fightinginflammation, ever since Hippocrates prescribed it in the form ofwillow bark tea. When aspirin fails to provide continued relief forchronic arthritis, rheumatologists often inject gold, in the form of goldsalts, into the swollen joints. This treatment goes back to 1927 whengold was thought to block the tuberculosis bacillus, an infection thenthought to cause arthritis.Just how gold works against inflammation remains unknown, but apaper in today's Nature lifts a corner of the precious metal'stherapeutic secret. The report, by an 11-person research team at VertexPharmaceuticals, Inc. in Cambridge, Mass., is titled "Structure andmechanism of interleukin-1b converting enzyme."This enzyme, explained the paper's principal author, enzymologistDavid Livingston, is the tool a white cell uses to detach interleukin-1bfrom its precursor protein chain, and unleash it to help trigger theinflammation process. Finding a drug to inhibit the IL-1b convertingenzyme (ICE) by solving the peptide's structure has been the goal ofmany pharmaceutical and biotech companies, Livingston, who headsthe inflammation project at Vertex, told BioWorld Today."We're quite sure that we are the first to do so," he said, "and we'requite sure that we did it faster than a number of groups who have beenworking on it longer." It took the Vertex crew two years to pinpoint thethousands of atoms that comprise ICE."It was not an easy problem technically," Livingston said. "It turnedout this was a very tricky enzyme to express and purify andcrystallize."A multidisciplinary group at Vertex _ led by X-ray crystallographerKeith Wilson, the paper's first author, solved the high-resolutionatomic architecture of the cytokine-converting enzyme, and in theprocess made several discoveries about its molecular structure.This included precise atomic details of ICE's active site, Livingstonadded, "that are now allowing us to do real structure-based rationaldrug design."Jointly with the company's French partner, Roussel-Uclaf, Livingstoncontinued, "we're now in the process of crystallizing lots of enzymeinhibitor complexes with ICE. And that's what we'll be doing probablyfor the next two years or so, before we have compounds we wouldregard as serious clinical candidates."Already, they have tried several such ICE inhibitors in mice, withresults as yet unpublished. "The message of these experiments,"Livingston said, "is that we have some very interesting and positiveinformation, showing that even a prototype ICE inhibitor can havesignificant therapeutic effect in an animal inflammation model." Hewent on, "These are clearly not drugs, because one has to give themstill in very high doses, and not yet available for oral administration.But they are very specific ICE inhibitors, and prove our concept."One surprise that came out of the team's study was the fact that the ICEmolecule can take the form of a tetramer _ a quaternary or quadruplemolecule. The Vertex researchers suspect that this tetramerization islinked somehow to activation of the IL-1b precursor inside the whiteblood cell.How they discovered that blocking this quadrupling will block ICEactivity is a story in itself, Livingston recalls: "One of the Naturepaper's co-authors, who worked on the ICE project in Vertex, sufferedfrom chronic rheumatoid arthritis, for which she took injections of goldsalts."At one point the sufferer suggested, `Gee, why don't we try these goldcompounds as ICE inhibitors?' We did, and it did."Livingston made the point that "The mode of action of goldcompounds is a mystery. But it is known that they affect blood levelsof cytokines, including IL-1."The team also determined that gold and other compounds bind to ICEat a point outside its active site, which suggests that these agents inhibitthe enzyme by preventing formation of the tetramer.Livingston hastens to add, "We're not claiming that this is necessarilythe only mechanism, but we do think it may be one of the importantmolecular modes of action." By using the structural information gainedin elucidating the atomic structure, he said, "we may be able to designnew kinds of anti-inflammatories, which probably won't be goldcompounds at all, but might inhibit ICE in the same way."He cited new findings that elevated levels of IL-1b have been found inthe blood of patients with neurodegenerative disease, and that anti-inflammatory drugs seem to prevent or postpone early onsetAlzheimer's. "We have every reason to believe," he said, "that it is ICEwithin the central nervous system that helps to produce these raisedlevels. If one had a compound that could penetrate the blood-brainbarrier, one might be able to treat the symptoms of these diseases."Noting that Vertex's solving of the ICE atomic structure "was a verytherapeutic-driven project," Livingston observed that "the anti-inflammatories are a huge market, and there is a real need for improveddrugs, which can deal with the upstream phase of the inflammatoryprocess, where the cytokines emerge, rather than the end of thepathway, where aspirin, ibuprofen, and the other current compounds dowhat they can." n

-- David N. Leff Science Editor

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