mp300707a_si_001.pdf (1.54 MB)
Physicochemical and Biological Characterization of Synthetic Phosphatidylinositol Dimannosides and Analogues
journal contribution
posted on 2013-05-06, 00:00 authored by Madlen Hubert, Benjamin
J. Compton, Colin M. Hayman, David S. Larsen, Gavin F. Painter, Thomas Rades, Sarah HookNative phosphatidylinositol mannosides
(PIMs), isolated from the
cell wall of Mycobacterium bovis, and synthetic PIM
analogues have been reported to offer a variety of immunomodulating
properties, including both suppressive and stimulatory activity. While
numerous studies have examined the biological activity of these molecules,
the aim of this research was to assess the physicochemical properties
at a molecular level and correlate these characteristics with biological
activity in a mouse model of airway eosinophilia. To accomplish this,
we varied the flexibility and lipophilicity of synthetic PIMs by changing
the polar headgroup (inositol- vs glycerol-based core) and the length
of the acyl chains of the fatty acid residues (C0, C10, C16, and C18).
A series of six phosphatidylinositol dimannosides (PIM2s) and phosphatidylglycerol dimannosides (PGM2s) were
synthesized and characterized in this study. Langmuir monolayer studies
showed that surface pressure–area (π–A) isotherms were greatly influenced by the length of the lipid acyl
chains as well as the steric hindrance and volume of the headgroups.
In aqueous solution, lipidated PIM2 and PGM2 compounds were observed to self-assemble into circular aggregates,
as confirmed by dynamic light scattering and transmission electron
microscopic investigations. Removal of the inositol ring but retention
of the three-carbon glycerol unit maintained biological activity.
We found that the deacylated PGM2, which did not show self-organization,
had no effect on the eosinophil numbers but did have an impact on
the expansion of OVA-specific CD4+ Vα2Vβ5 T
cells.
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Keywords
headgroupairway eosinophilialipid acyl chainsPIM 2sPGM 2 compoundsphosphatidylglycerol dimannosidesSynthetic Phosphatidylinositol DimannosidesPIM analoguestransmission electronmouse modelPGM 2sacyl chainsBiological CharacterizationMycobacterium bovislengthacid residueseosinophil numbersAnaloguesNative phosphatidylinositol mannosidesphysicochemical propertiescell wallsteric hindrancelipidated PIM 2immunomodulating propertiesLangmuir monolayer studiesinositol ringphosphatidylinositol dimannosides
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