If the experimental data reported in last week's Naturetranslate from rats to humans, carbohydrate analogs beingdeveloped by Cytel Corp. may be useful in reducing the tissuedamage associated with certain inflammatory diseases,University of Michigan researcher Peter Ward and hisassociates at the Howard Hughes Medical Institute in AnnArbor and Cytel of San Diego tested a number ofoligosaccharide analogs of sialyl Lewis X (SLex), thecarbohydrate found on the surface of neutrophils.
SLex has been shown to bind to selectin receptors that arefound on the cells lining the blood vessel wall at a site ofinflammation. It is thought that the binding of SLex to P- (or E-) selectin receptors helps the neutrophils "roll" along the bloodvessels and into the surrounding tissue.
The researchers found that if they blocked these selectinreceptors with SLex analogs either prior to or very shortlyafter they administered an agent that causes acute lung injury(cobra venom factor) to experimental rats, they were able toreduce neutrophil accumulation in the lungs as well as overalldamage to that tissue by at least 40 percent. These results heldfor three different SLex analogs, but not for an unrelated non-fucosylated sugar.
Ward and his colleagues found that all three analogs exhibiteddose-dependent effects, the maximal at 200 micrograms total(which translates to a blood concentration of less than 1 uM inthe rat model), which fell off sharply if the analogs wereadministered more than five minutes after the CVF.
"This is consistent with what's known about P-selectinexpression, which occurs within minutes," said Jay Kranzler,Cytel's president and chief executive officer. "We need to treat(with the SLex analog) either way before or immediatelybefore P-selectin gets expressed," he added.
Ward's acute lung injury rat model could serve as a predictorof adult respiratory distress syndrome (ARDS) in humans. Infact, Cytel (NASDAQ:CYTL) is developing its SLex analogs fortreating ARDS and other inflammatory diseases as well asreperfusion injury.
Company scientists have devised a technology to manufacturethe oligos in large quantities, even kilograms. The methodcombines enzymatic and organic syntheses in a three-partprocess that reduces production costs by "two to three ordersof magnitude" over the traditional 40-60 step method,according to James Paulson, Cytel's vice president of researchand one of the inventors of the technology.
Cytel said it expects to file an investigational new drug (IND)application on CY1503, an SLex analog not described in theNature paper for treating reperfusion injury this year, Kranzlertold BioWorld.
-- Jennifer Van Brunt Senior Editor
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