alexa Toward the discovery of vaccine adjuvants: coupling in silico screening and in vitro analysis of antagonist binding to human and mouse CCR4 receptors.
Materials Science

Materials Science

Journal of Nanomedicine & Biotherapeutic Discovery

Author(s): Davies MN, Bayry J, Tchilian EZ, Vani J, Shaila MS, , Davies MN, Bayry J, Tchilian EZ, Vani J, Shaila MS, , Davies MN, Bayry J, Tchilian EZ, Vani J, Shaila MS, , Davies MN, Bayry J, Tchilian EZ, Vani J, Shaila MS,

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Abstract BACKGROUND: Adjuvants enhance or modify an immune response that is made to an antigen. An antagonist of the chemokine CCR4 receptor can display adjuvant-like properties by diminishing the ability of CD4+CD25+ regulatory T cells (Tregs) to down-regulate immune responses. METHODOLOGY: Here, we have used protein modelling to create a plausible chemokine receptor model with the aim of using virtual screening to identify potential small molecule chemokine antagonists. A combination of homology modelling and molecular docking was used to create a model of the CCR4 receptor in order to investigate potential lead compounds that display antagonistic properties. Three-dimensional structure-based virtual screening of the CCR4 receptor identified 116 small molecules that were calculated to have a high affinity for the receptor; these were tested experimentally for CCR4 antagonism. Fifteen of these small molecules were shown to inhibit specifically CCR4-mediated cell migration, including that of CCR4(+) Tregs. SIGNIFICANCE: Our CCR4 antagonists act as adjuvants augmenting human T cell proliferation in an in vitro immune response model and compound SP50 increases T cell and antibody responses in vivo when combined with vaccine antigens of Mycobacterium tuberculosis and Plasmodium yoelii in mice.
This article was published in PLoS One and referenced in Journal of Nanomedicine & Biotherapeutic Discovery

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