Although it is widely appreciated that host and pathogen derived glycoconjugates play key roles in infection and immunity, molecular details of these processes are often difficult to dissect due to the structural complexity and heterogeneity of glycoconjugates. Synthetic chemistry has the promise of providing panels of well-defined glycoconjugates for structure-activity relationship studies, which will provide important insights into the molecular aspects of host-pathogen interactions and offer opportunities for the development of new therapies for the treatment of many diseases including infection, atherosclerosis, arthritis and cancer. Detailed structure- activity relationship studies require synthetic strategies that will give easy access to panels of well-defined glycoconjugates. We propose to develop such approaches for the synthesis of libraries of lipopolysaccharides (LPS), glycosylphosphatidylinositol (GPI) anchors and chondroitin sulfates (CS), and employ the resulting compounds to examine in detail the molecular aspects of several infectious and innate immune processes. Microbial components such as LPS of Gram-negative bacteria and GPIs of parasites are recognized by receptors of the innate immune system of the host resulting in defense responses. Although these responses are beneficial to the host, over-activation of the innate immune system can be harmful;for example, the GPI of the parasite P. falciparum has been linked to excessive production of cytokines leading to the pathology of malaria. Furthermore, LPS in blood of infected patients has been linked to sepsis. Guided by a recent X-ray crystal structure of MD2-TLR4 with LPS, a range of synthetic lipid As will be prepared which will be examined for binding, dimerization of the MD2-TLR4 receptor complex and their ability to induce the production of a range of cytokines. We expect to dissect the structural features responsible for high affinity binding and cellular activation, which in turn will provide opportunities for the design of antagonists or immune modulators. Furthermore, a synthetic strategy for the preparation of a panel of GPI anchors will be devised, which will be employed to determine structural features of parasitic GPI responsible for inducing inflammatory responses. Red blood cells infected with the parasite P. falciparum can accumulate in the placenta due to their capacity to bind CS resulting in pregnancy-associated malaria. CS binding has been linked to the adhesion protein var2CSA, which is expressed by the parasite when it multiplies in red blood cells and then exposed on the erythrocyte cell-surface. It is to be expected that CS oligosaccharides that bind with high affinity to var2CSA can inhibit the adhesion of P. falciparum infected red blood cells to the placenta thereby providing a novel modality for the treatment of pregnancy-associated malaria. A modular approach for the synthesis of CS will be developed that employs a set of properly protected disaccharide building blocks that resemble the different disaccharide motives found in CS, and can repeatedly be used for the preparation of multiple targets. The new methodology will be employed to probe the ligand requirements of var2CSA and several chemokines.
Host and pathogen derived complex carbohydrates play key roles in infection and immunity. Although it has been realized that molecular details of host-pathogen interactions involving complex carbohydrates offer exciting opportunities for drug discovery, such research programs have been complicated by difficulties of obtaining well-defined complex carbohydrates for structure-activity relationship studies. We will address this problem by developing efficient approaches for the chemical synthesis of libraries of lipopolysaccharides, glycosylphosphatidylinositol anchors and chondroitin sulfates, and employ these complex carbohydrates to examine in detail the molecular aspects of several infectious and innate immune processes.
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