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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.

Original publication

DOI

10.1371/journal.pone.0008084

Type

Journal article

Journal

PLoS One

Publication Date

30/11/2009

Volume

4

Keywords

Adjuvants, Immunologic, Animals, Antigens, CD4-Positive T-Lymphocytes, Cattle, Cell Movement, Computational Biology, Down-Regulation, Humans, In Vitro Techniques, Interleukin-2 Receptor alpha Subunit, Mice, Mycobacterium tuberculosis, Plasmodium yoelii, Protein Binding, Receptors, CCR4, T-Lymphocytes, Regulatory, Vaccines