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Faculty Chemokines and Their Diverse Biological Paradigms
Scientific advances continue to identify members of the chemokine supergene families as biologically diverse mediators of important immunologic and physiologic events. While initial investigations originally defined the biological activity of chemokines as proteins with novel chemotactic activity for specific sub-populations of leukocytes, data now supports a much broader biological role for the chemokines. The chemotactic activity of chemokines for specific leukocyte sub-populations is, in itself, an important activity, as this response provides a mechanism for the successful delivery of the appropriate leukocyte population from the lumen of the vasculature to a site of inflammation. This biological response provides the means for the accumulation of either granulocytes at foci of acute inflammation, via the activity of CXC chemokines, or the accumulation of mononuclear cells at foci of chronic inflammation, via the activity of CC chemokines. However, leukocyte chemotaxis may not be the only, or the most important, activity of the chemokine family members. A variety of reports have stressed the key role of chemokines in a variety of physiologic and pathologic situations, which may provide mechanisms for activating cytokine networks, altering the expression of adhesion molecules, increasing cell proliferation, regulating angiogenesis, promoting viral-target cell interactions, increasing hematopoiesis, stimulating mucus production, increasing the metastatic potential of tumor cells and activating the innate immune system. The importance of chemokines as a contributing player to the immune response is further underscored by investigations that have identified viral genes that encode chemokine binding proteins. Importantly, chemokines have been shown to participate in the progression of chronic inflammation by influencing mononuclear cell chemotaxis, hematopoiesis, angiogenesis, stromal cell proliferation, matrix deposition and lymphocyte polarization. This latter activity is especially important, as specific chemokine ligand/receptor pairs have been identified in type 1 (Th1) versus type 2 (Th2) immune responses. These observations have played an important role in the design of efficacious small molecular weight antagonists to therapeutically target specific chemokine receptors, as these receptors and their ligands are likely to participate in the evolution of chronic immune responses. Chemokine Receptor Antagonists: Promising New
Therapies Chemokine receptors belong to one of the most pharmacologically exploited family of proteins: the G-protein coupled receptors (GPCRs). Drugs that target these receptors make up greater than 45% of all known-marketed medicines. Collectively the chemokines because of their important role in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis have been the focus of much attention by drug companies and almost all of the major pharmaceutical houses have screens to identify chemokine receptor antagonists. The promise of highly specific therapies for a number of devastating diseases is now on the horizon thanks to the identification of specific chemokine receptor antagonists and this presentation will focus on the progress we have made in identifying these potentially promising drugs with detailed reference to the CCR1 antagonist from Berlex, BX 471. CCR5 antagonists for HIV therapy CCR5 Antagonists for HIV describes the drug discovery
programme that led to the identification of UK-427,857, a prototype
CCR5 antagonist with excellent potency against lab-adapted and primary
virus strains, as a clinical candidate for the treatment of HIV. In
particular, it deals with strategies for minimising cardiac toxicity
whilst marinating ADME properties commensurate with low dose. |
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