Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.6/3910
Título: Small-molecule boron compounds to use against interleukin-23
Autor: Antunes, Joana Alexandra Pereira
Orientador: Tomaz, Cândida Ascensão Teixeira
Freund, Yvonne
Palavras-chave: Química médica
Psoríase - Citocinas - Quimiociones
Inibidores PDE4
Data de Defesa: 2008
Resumo: Anacor Pharmaceutical’s core technology platform is based on the use of boron chemistry to develop novel therapies. Boron-based compounds have a unique geometry that allows them to have two distinct shapes, giving boron-based drugs the ability to interact with biological targets in novel ways and to address targets not amenable to intervention by traditional, carbon-based compounds. Boron’s reactivity allows boronbased compounds to interact with a biological target that is specific to a particular disease or condition and create a change in that target. The anti-inflammatory properties of some Anacor compounds merged with research in the etiology of psoriasis could improve this pathological condition. Initially the origin of psoriasis was attributed to keratinocytes, but nowadays is a known fact that it’s the close relationship between those cells and several others immune cells that creates the symptoms and typical lesions of this pathology – well-demarcated erythematous, scaly plaques with epidermal hyperplasia (acanthosis) accompanied by parakeratosis. Analysis of the cell infiltrates as well as the type of cytokines and chemokines present in the psoriatic lesions, first lead researchers to believe that this was either a T helper 1 (TH1) disease (due to the high levels of Interleukin-12 (IL-12) and Interferon-γ (IFN-γ) and CD4+ cells) or an autoimmune disease (where the immune system would auto-react against own keratinocytes). With the discovery of a novel cytokine – Interleukin-23 (IL- 23) - that shares the p40 subunit with IL-12 and also the IL-12Rβ1 receptor, but not the IL-23R, a new possible path was initiated. Unlike IL-12, the new discovered cytokine – IL-23 does not act on naïve T cells, but it does act on memory T cells. The IL-12 initially found in psoriatic lesions is actually IL-23 and a relationship was build between this and another cytokine – Interleukin -17 (IL-17). Further research lead to the findings of a CD4+ subset that produces IL-17 (and other important cytokines) which was then designated T helper 17 (TH17). IL-23 is responsible for maintaining the growth of this subset of immune cells and both IL-23 and TH17 were implicated in psoriasis. Due to the structural similarity with IL-12, it was thought that the same inhibitory mechanisms that inhibit IL-12 could also inhibit IL-23 production. Phosphodiesterase 4 (PDE4) is the major cyclic AMP (cAMP)-metabolizing enzyme found in inflammatory and immune cells. Therefore and since there’s a wide range of cytokines whose production is inhibited by PDE4 inhibitors, Structure Activity Relationship (SAR) was built having IL-23 inhibition data along with PDE4 inhibition data for Anacor compounds and commercially available compounds known to inhibit PDE4 (i.e. Rolipram, Ibudilast and others). The present work shows that the PDE4 inhibition does not correlate with IL-23 inhibition, not just by the fact that there are several compounds that inhibit the cytokine but not the enzyme and the other way around, but also because the commercially available compounds known to inhibit the PDE4 do not inhibit IL-23 production. Investigating further on and continue to look for IL-23 inhibition by structurally different chemical compounds synthesized as well as trying to understand the pathways by which IL-23 is produced would hopefully in the future increase the amount of information available about this cytokine regulation.
URI: http://hdl.handle.net/10400.6/3910
Designação: Mestrado em Bioquímica
Aparece nas colecções:FC - DQ | Dissertações de Mestrado e Teses de Doutoramento

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Thesis - Annex I - Results Tables.pdf412,75 kBAdobe PDFVer/Abrir
Thesis - Main Document.pdf1 MBAdobe PDFVer/Abrir

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