Glucan glycomimetics: A new approach to stimulating innate immune training - Abstract For many years it was thought that “immunologic memory” cannot be induced within the innate immune system. However, recent research challenges this long held dogma. There is now compelling evidence that the innate immune system can be “trained” to respond more rapidly and effectively to pathogens. These findings challenge the existing paradigm that innate immunity cannot develop “memory” or be “trained” to respond more effectively to infection and indicate that “trained immunity” can be harnessed to increase resistance to infection. Trained immunity elicits broad resistance to infection that persists for weeks to months and is not specific with respect to the causative agent. The development of immune training drugs would make it possible to harness the potential of trained immunity for the treatment of disease. β-Glucan, a fungal cell wall constituent, confers resistance to infection with Gram-negative and Gram-positive bacteria as well as viral and fungal pathogens. Numerous studies have shown that β-glucans will induce innate immune training. In fact, β-glucans are now recognized as the “gold standard” for induction of the immune trained phenotype. However, β-glucan is a natural product that is isolated from fungal sources. Large scale isolation of natural product β-glucans is plagued by QA/QC problems and reproducibility issues. This is due in large part to the fact that all natural product β-glucans are a distribution of glucan polymers with varying polymer lengths and, in some cases, differences in branching frequency, length of side chain branches and solution conformation. What was needed were methods for the complete chemical synthesis of (1→3,1→6)-β-glucans with specific structural characteristics including polymer size, side chain branching frequency, side chain branch length, etc. We have successfully developed convergent synthetic approaches for the de novo synthesis of (1→3,1→6)-β-glucans with specific structural characteristics. The goals of this research are to: i) evaluate the ability of synthetic glucan glycomimetics to induce the immune trained phenotype and ii) to compare and contrast the bioactivity of different glucan glycomimetic formulations to natural product glucans. We hypothesize that synthetic glucan glycomimetics will induce the trained immune phenotype similar to natural product glucans. To critically evaluate this hypothesis we propose the following specific aims. Aim 1. Assess the ability of glucan glycomimetics to induce the immune trained phenotype. Aim 2. Examine the immune training ability of glucan glycomimetics conjugated to silica nanoparticles. A successful conclusion to this research will result in the identification of synthetic (1→3,1→6)-β-glucan glycomimetics that will induce the immune trained phenotype in human immunocytes. This will lead to the development of glycomimetic drug candidates that can prophylactically and/or therapeutically induce immune training and alter the course of disease. In addition, a successful conclusion to this research will result in new and novel data on the structure activity relationships of glucans in trained immunity.
