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antisense strand hybridizes the complementary mRNA to form a double-stranded helix thereby
achieving the inhibition of the gene products. Antisense oligo-deoxynucleotide derivatives have been
shown to inhibit species-specific fibroblast PGE 2 synthesis stimulated by IL-1. These approaches
generated much interest and many laboratories are pursuing the design of compounds based on antisense
nucleotides, triple-helical transcription inhibitors, aptamers, and other novel nucleic acid derivatives.
V. Neutralizing Soluble IL-1 in Circulation
Once IL-1 is released into the extracellular fluid, the following molecules can be employed to
manipulate its activity: soluble receptors, IL-1Ra, IL-1 neutralizing antibodies, IL-1-specific binding
proteins, high-affinity small molecules (Figure 10).
A. Soluble IL-1 Receptors
The most effective neutralizer of a cytokine is likely to be its receptor. Some viruses have been reported
to use an IL-1 receptor mimic to evade the immune system [72]. Natural shedding of cytokine receptors
is a common occurrence and may form part of a normal homeostatic regulatory system, and there is a
high potential for the use of such soluble forms as therapeutic agents. The binding affinity of the mature
forms of the interleukin-1 molecules and their receptors have been reported [8,31–33,71]. These studies
show that the affinity of both the membrane-bound and soluble forms of human IL-1RI for the mature
forms of human IL-1α, IL-1β, and IL-1Ra are approximately the same. In contrast to IL-1RI, IL-1RII
binds IL-1βpreferentially. Based on the binding-affinity studies one can infer that soluble IL-1RI is a
better inhibitor of IL-1α than IL-1β and soluble IL-1RII is a better inhibitor of IL-1β. Both soluble
receptors, at sufficiently high concentrations, will completely block the binding of both IL-1 forms to
cells. Dower and coworkers [8] have studied the real-time binding of human IL-1α, IL-1β, and IL-1Ra
to human soluble IL-1RI and IL- 1RII. It seems that the binding of IL-1Ra to IL-1RI is essentially
irreversible, whereas its binding to IL-1RII is rapidly reversible. In contrast, IL-1RII binds IL-1β
irreversibly [8,1]. This indicates that the IL-1RII can be used as a high-affinity antagonist of IL-1β.
Dower further suggest in his studies that the soluble receptors have several potential advantages over
anticytokine antibodies due to the fact that they have much higher affinities (100 to 1000 fold) and
should not be recognized by the immune system. Even though soluble receptors have high-binding
affinity they are difficult to synthesize in large quantities and they have a low half-life.
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