Jagadeesh Bayry

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

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.

Dissecting the Anti-Inflammatory Effects of Viscum album: Inhibition of Cytokine-Induced Expression of Cyclo-Oxygenase-2 and Secretion of Prostaglandin E2

Reports unraveling the beneficial effects of Viscum album (VA) preparations as complementary therapies for cancer have increasingly revealed the underlying molecular and cellular mechanisms, which encompass cytotoxic properties, induction of apoptosis, inhibition of angiogenesis and several other immunomodulatory mechanisms. In addition to their propitious relevance to cancer therapy, VA preparations are also relevant for the treatment of several inflammatory pathologies. In view of the intricate association of inflammation and cancer and the fact that several anti-tumor phytotherapeutics exert potent anti-inflammatory effects, we believe that an anti-inflammatory effect is responsible for the therapeutic benefits of VA preparations. One of the underlying molecular mechanisms of this inflammatory response is the selective down-regulation of the cyclo-oxygenase (COX)-2-mediated cytokine-induced secretion of prostaglandin E2 (PGE2). This inhibitory action has been associated with reduced expression of COX-2, without modulating COX-1 expression. This mechanism is associated with VA-induced destabilization of COX-2 mRNA, thereby depleting the functional COX-2 mRNA available for protein synthesis and for subsequent induction of secretion of PGE2. Together, these results demonstrate a novel anti-inflammatory mechanism of action of VA preparation, wherein VAQUSpez an anti-inflammatory effect by inhibiting cytokine-induced PGE2 via selective inhibition of COX-2 and destabilization of COX-2 mRNA.