title: Solution and solid-support synthesis of a potential leishmaniasis carbohydrate vaccine.
abstract: The synthesis of a potential carbohydrate vaccine for the parasitic disease leishmaniasis is described. New solution- and solid-phase synthetic strategies were explored for the assembly of a unique tetrasaccharide antigen found on the Leishmania lipophosphoglycan. An initial solution-phase synthesis relied on thioglycosides as building blocks and the establishment of the central disaccharide from lactal via an oxidation-reduction sequence. A second approach was completed both in solution and on solid support. The solid-phase synthesis relied on assembly from monosaccharide units and was used to evaluate different glycosylating agents in the efficient installation of the galactose beta-(1-->4) mannoside. Glycosyl phosphates proved most successful in this endeavor. This first solid-phase synthesis of the Leishmania cap provided rapid access to the tetrasaccharide in 18% overall yield while requiring only a single purification step. The synthetic cap tetrasaccharide was conjugated to the immunostimulator Pam3Cys to create fully synthetic carbohydrate vaccine 1 and to the carrier protein KLH to form semisynthetic vaccine 2. Currently, both constructs have entered initial immunological experiments in mice targeted at the development of a vaccine against the parasitic disease leishmaniasis.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Hewitt
authors.forename: P H
authors.initials: PH
authors.lastname: Seeberger
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D002240:Carbohydrate Sequence; D006028:Glycosphingolipids / Q000737:chemistry / Q000276:immunology; D007891:Leishmania / Q000276:immunology; D007896:Leishmaniasis / Q000517:prevention & control*; D051379:Mice; D008969:Molecular Sequence Data; D016052:Protozoan Vaccines / Q000008:administration & dosage / Q000138:chemical synthesis*; D013057:Spectrum Analysis
chemical_list: D000953:Antigens, Protozoan; D006028:Glycosphingolipids; D016052:Protozoan Vaccines; C008290:lipophosphonoglycan