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Rational Drug Design - A number of strategies can be utilised to design antagonists to the FcyRlla/IgG interaction. These involve screening of peptide or non-peptide combinatorial libraries, phage display or use of anti-receptor antibodies. An alternative strategy is to use a structure based drug design approach to the development of small chemical antagonists specific for FcyRlla. The structure of FcyRlla demonstrates that this receptor is a dimer in contrast to the highly related FcyRllb or the FcyRI or FcyRIII (6, 32). Thus, the receptor has several features that make it amenable to drug design. The IgG binding sites of each monomer are juxtaposed and, in the dimerization process, a well defined groove is created that abuts the binding sites and also creates a hole about the two-fold axis of symmetry (Figure 2). The groove - approximate dimensions of 23x7x6 Angstrom tapering to a 4-Angstrom groove floor - together with the binding site provides several suitable target areas for drug design. A variety of side chains, including those involved in the interaction with IgG, are juxtaposed and were the initial targets for the drug design process especially phenylalanine (Phe124) and lysine (Lys ) (5,21-27). As an initial screen, libraries of compounds were docked into the groove of the receptor such that interactions involved the phenylalanine and lysine. Such screening generated a number of compounds that were further modified and tested in the screening assays.

In vitro Screening - The choice of screening assays for FcyRlla receptor antagonists is of prime importance. Since the physiological role of dimerization or their point of association in cells is not known, conventional assays utilising immobilised receptor assays is a poor choice. We have utilised two assays based on human platelets, as FcyRlla is the only Fc receptor expressed on these cells. Such a choice can overcome the interference caused by the other Fc receptors. Binding of heat aggregated human immunoglobulin (HAGG) or immune complexes to FcyRlla receptors on platelets activates them and induces the expression of P-selectin, which can be measured by flow cytometry and is utilised as one of the assay systems. The platelet aggregation assay can also be utilised, as aggregation is the final endpoint of activation of platelets by immune complexes. Specificity controls include a number of other agonists such as ADP, arachidonic acid or collagen that aggregate platelets via a non-FcyRlla receptor.

In Vivo Efficacy - FcyRlla is absent in mice and receptor antagonists cannot be tested in inbred strains of mice. A transgenic mouse expressing FcyRlla could be used for in vivo evaluation of receptor antagonists. The collagen-induced arthritis model (CIA) is used as an in vivo model for evaluating anti-arthritic drugs (33). Even though the strain of transgenic mice is on a resistant H-2b haplotype, these mice develop CIA with similar features of the disease to the DBA/1 strain. As the transgenic mice also express FcyRlla on platelets (as in humans), the same mice can be used to test the efficacy of the inhibitors against immune thrombocytopenia.


The solved 3D structures of complexes of human FcyRIII and lgG1, human FceRI and IgE also offer opportunities in the design of antagonists of receptorlg interactions. In both cases, no receptor dimer is indicated and, indeed, the complexes show interactions over a broad surface which is largely featureless. Such arrangements make design of effective small chemical entities (SCE) difficult which is a general problem in protein receptor: protein ligand interactions. Nonetheless with the advent of modern chemistries, the possibilities of targeting multiple sites with multispecific SCEs maybe possible.

The case for targeting the IgE receptor is clear - inhibition of the lgE:FceR1 interaction will inhibit allergic reactions but the extraordinary high affinity (>10"1° M"1) makes the practical use of any SCE in receptor: ligand antagonism problematic. In the case of FcyRIII, the case for it as a target in autoimmunity remains to be clarified. All mouse studies to date have been performed in the absence of FcyRlla. The features - structurally, biochemically and biologically that make FcyRlla the "ideal" target (described above) are sufficiently compelling to warrant targeted effort against this receptor in the development of novel anti-inflammatories.

Conclusion - The increasing body of evidence that Fc receptors are key receptors in the development of inflammation caused by immune complexes now makes these valid targets for new therapeutics in the treatment of autoimmune diseases and in the case of the IgE receptor, allergy. The powerful revolution in drug discovery and development technologies especially in relation to structure based approaches now enables an entirely or partly rational approach to the generation of receptor antagonists. It is clear in the immediate future that the design of compounds directed towards the uniquely human FcyRlla with its dominant role in activation of platelets and leucocytes by immune complexes will be fertile ground for novel antiinflammatory approaches.


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