Toward the Discovery of Vaccine Adjuvants: Coupling In Silico Screening and In Vitro Analysis of Antagonist Binding to Human and Mouse CCR4 Receptors

Davies, Matthew N and Bayry, Jagadeesh and Tchilian, Elma Z and Vani, Janakiraman and Shaila, Melkote S and Forbes, Emily K and Draper, Simon J and Beverley, Peter CL and Tough, David F and Flower, Darren R (2009) Toward the Discovery of Vaccine Adjuvants: Coupling In Silico Screening and In Vitro Analysis of Antagonist Binding to Human and Mouse CCR4 Receptors. In: PLoS ONE, 4 (11).

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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 cellmigration, 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.

Item Type:	Journal Article
Publication:	PLoS ONE
Publisher:	Public Library of Science
Additional Information:	Copyright for this article belongs to Public Library of Science.
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	06 Jan 2010 12:00
Last Modified:	19 Sep 2010 05:54
URI:	http://eprints.iisc.ac.in/id/eprint/25329

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