Modulation of Innate Immune Responses: Synthesis and Biological Studies of Homo- and Hetero-dimeric Pattern Recognition Receptor Agonists and Other Immunostimulants

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Immune cells defend against microbial infection by detecting pathogen-associated molecular patterns (PAMPs) present on microbes via pattern recognition receptors. Harnessing signalling by targeting these receptors with small molecule immunostimulants could greatly benefit the development of effective therapeutic agents. Although a good number of immunostimulants are known to date, the translation of these molecules into clinical uses is challenging for a number of reasons, such as: (a) a lack of understanding of the exact mechanisms of their action, and thus the inability to precisely predict effects, (b) relatively low potency of some immunostimulants, and (c) toxic side effects of others. In this research, we propose to covalently link different immunostimulants in order to study the effects of particular combinations of such molecules on their immunological properties. Covalently linked dimeric ligands containing two immunostimulants can simultaneously target two receptors of the immune system. Such dimeric ligands thereby become more potent immune activating agents due to a synergistic effect between the two immunostimulants. A group of dimeric ligands comprised of several different types of immunostimulants and different lengths of linking spacers will be chemically synthesized. Biological studies using in vitro experiments will reveal the immunostimulatory activity of these compounds. This research will provide useful tools for binding immunostimulating molecules to study innate immune response to synthetic immunostimulants and the crosstalk mechanisms between receptors. Through chemical synthesis and biological studies, more potent immunostimulants with no toxic side effects will be discovered. The long term goal of this research is to discover novel immunostimulatory agents with high potency and defined immunological effects, which will provide useful molecular tools for health-related research and ultimately lead to the development of clinically useful therapeutic agents such as vaccine adjuvants.