Total synthesis of tetraacylated phosphatidylinositol hexamannoside and evaluation of its immunomodulatory activity

Abstract

Tuberculosis, aggravated by drug-resistant strains and HIV co-infection of the causative agent Mycobacterium tuberculosis, is a global problem that affects millions of people. With essential immunoregulatory roles, phosphatidylinositol mannosides are among the cell-envelope components critical to the pathogenesis and survival of M. tuberculosis inside its host. Here we report the first synthesis of the highly complex tetraacylated phosphatidylinositol hexamannoside (Ac2PIM6), having stearic and tuberculostearic acids as lipid components. Our effort makes use of stereoelectronic and steric effects to control the regioselective and stereoselective outcomes and minimize the synthetic steps, particularly in the key desymmetrization and functionalization of myo-inositol. A short synthesis of tuberculostearic acid in six steps from the Roche ester is also described. Mice exposed to the synthesized Ac2PIM6 exhibit increased production of interleukin-4 and interferon-γ, and the corresponding adjuvant effect is shown by the induction of ovalbumin- and tetanus toxoid-specific antibodies.

C-Type Lectin Receptor DCAR Recognizes Mycobacterial Phosphatidyl-Inositol Mannosides to Promote a Th1 Response during Infection

“…PIM2 and synthetic PIM2 analogs have been designed for use of experimental adjuvants (Ainge et al, 2006;Parlane et al, 2012;Patil et al, 2015;Sprott et al, 2004;Zheng et al, 2015). The identification of a novel PIM2 receptor may provide a molecular basis for the development of efficient adjuvants for therapeutic vaccines against not only tuberculosis but also other infectious diseases, and cancer.…”

Structural basis for safe and efficient energy conversion in a respiratory supercomplex

“…The glycolipids lipomannan and AcPIM 2 are native constituents of the cell envelope of the Corynebactereae family that includes pathogenic M. tuberculosis 28 , 29 . They contribute to the low permeability of the cell envelope and the intrinsic tolerance against antibiotics 30 and can sabotage immunoregulatory responses 31 . In addition, a lycopene molecule is resolved in a narrow tunnel of QcrB close to the Q o site and with access to the intercomplex cavity (Fig.…”

The Research Progress in Immunotherapy of Tuberculosis

“…It can also activate NKT cells together with CD1 molecules to produce IFN-γ, interact with α5β1 on CD4 + T cells to promote granulomatous formation and promote alveolar epithelial cell apoptosis ( Rojas et al., 2006 ). Recent research has shown that tetraacylated phosphatidylinositol hexamannoside (Ac2PIM6), which is synthesized with stearic and tuberculostearic acid as the lipid components, could increase the production of IL-4 and IFN-γ in mouse serum and have comparable adjuvant activity ( Patil et al., 2015 ). Therefore, the immunotherapeutic effect of PIMs on TB requires further verification.…”