The prevalence of immune-evading diseases has lead to the emergence of immunotherapies. The challenge for developing improved immunotherapies is designing vaccines that are highly targeted and will generate lifelong immunity toward a disease. Vaccines typically consist of a target antigen and a single immune-stimulating agonist, where the agonist binds to receptors on antigen-presenting cells and helps target the antigen to these immune cells. Many vaccines are suboptimal, though, because the resulting immune response is incomplete. In recent years, more effective vaccines have been developed via the use of multiple agonists. The Toll-like receptors (TLRs) and their activating ligands are one of the most studied classes of receptors. Research suggests that the spatial proximity between and synergistic combinations of TLR agonists play a significant role in the activation of immune pathways. However, there continue to be questions about how and why agonist synergies affect immune system signaling and activation. Our research focuses on the interface between synthetic chemistry and immunology. Here, we present our progress toward the synthesis of a small molecule that can be conjugated to various agonists using orthogonal functional handles. Research has shown that three different nucleophiles can be substituted into cyanuric chloride simply by varying the reaction conditions. The triazine-based molecule will be employed to attach three agonists together. The orthogonal functional handles will provide a modular system where any agonist combination can be tested. This system presents a way to deliver multiple agonists and antigens to immune cells and modulate the immune response. From this, we can determine the mechanism by which these molecules activate the immune system and how these chemical structures affect the body's response. These chemical tools will allow us to learn more about how the immune system functions in order to design more potent and directed vaccines and address challenges in immunotherapy.

Synthesis and application of a multi-agonist triazine core used to study synergies in immune system stimulation

248th National Meeting (2014)

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