title: Chemical synthesis of all phosphatidylinositol mannoside (PIM) glycans from Mycobacterium tuberculosis.
abstract: The emergence of multidrug-resistant tuberculosis (TB) and problems with the BCG tuberculosis vaccine to protect humans against TB have prompted investigations into alternative approaches to combat this disease by exploring novel bacterial drug targets and vaccines. Phosphatidylinositol mannosides (PIMs) are biologically important glycoconjugates and represent common essential precursors of more complex mycobacterial cell wall glycolipids including lipomannan (LM), lipoarabinomannan (LAM), and mannan capped lipoarabinomannan (ManLAM). Synthetic PIMs constitute important biochemical tools to elucidate the biosynthesis of this class of molecules, to reveal PIM interactions with host cells, and to investigate the function of PIMs as potential antigens and/or adjuvants for vaccine development. Here, we report the efficient synthesis of all PIMs including phosphatidylinositol (PI) and phosphatidylinositol mono- to hexa-mannoside (PIM1 to PIM6). Robust synthetic protocols were developed for utilizing bicyclic and tricyclic orthoesters as well as mannosyl phosphates as glycosylating agents. Each synthetic PIM was equipped with a thiol-linker for immobilization on surfaces and carrier proteins for biological and immunological studies. The synthetic PIMs were immobilized on microarray slides to elucidate differences in binding to the dendritic cell specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN) receptor. Synthetic PIMs served as immune stimulators during immunization experiments in C57BL/6 mice when coupled to the model antigen keyhole-limpet hemocyanin (KLH).
authors.affiliation: Laboratory for Organic Chemistry, Swiss Federal Institute of Technology (ETH) Zürich, Wolfgang-Pauli-Str. 10, HCI F312, 8093 Zürich, Switzerland.
authors.forename: Siwarutt
authors.initials: S
authors.lastname: Boonyarattanakalin
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.forename: Mario
authors.initials: M
authors.lastname: Michieletti
authors.forename: Bernd
authors.initials: B
authors.lastname: Lepenies
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeberger
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D007294:Inositol / Q000737:chemistry; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000737:chemistry*; D010716:Phosphatidylinositols / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011134:Polysaccharides / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000378:metabolism; D013499:Surface Properties; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000276:Adjuvants, Immunologic; D015815:Cell Adhesion Molecules; D007294:Inositol; D037181:Lectins, C-Type; D010716:Phosphatidylinositols; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C034154:phosphatidylinositol mannoside