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Proc Natl Acad Sci U S A. 2013 May 28;110(22):8795-800. doi: 10.1073/pnas.1221708110. Epub 2013 May 13.

Mannodendrimers prevent acute lung inflammation by inhibiting neutrophil recruitment.

Author information

1
Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France.

Abstract

Mycobacterium tuberculosis mannose-capped lipoarabinomannan inhibits the release of proinflammatory cytokines by LPS-stimulated human dendritic cells (DCs) via targeting the C-type lectin receptor DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN). With the aim of mimicking the bioactive supramolecular structure of mannose-capped lipoarabinomannan, we designed and synthesized a set of poly(phosphorhydrazone) dendrimers grafted with mannose units, called mannodendrimers, that differed by size and the number and length of their (α1→2)-oligommanoside caps. A third-generation dendrimer bearing 48 trimannoside caps (3T) and a fourth-generation dendrimer bearing 96 dimannosides (4D) displayed the highest binding avidity for DC-SIGN. Moreover, these dendrimers inhibited proinflammatory cytokines, including TNF-α, production by LPS-stimulated DCs in a DC-SIGN-dependent fashion. Finally, in a model of acute lung inflammation in which mice were exposed to aerosolized LPS, per os administration of 3T mannodendrimer was found to significantly reduce neutrophil influx via targeting the DC-SIGN murine homolog SIGN-related 1. The 3T mannodendrimer therefore represents an innovative fully synthetic compound for the treatment of lung inflammatory diseases.

KEYWORDS:

ManLAM functional analogs; SIGNR1 targeting; antiinflammatory molecule; glycodendrimer synthesis; multivalent ligands

PMID:
23671078
PMCID:
PMC3670345
DOI:
10.1073/pnas.1221708110
[Indexed for MEDLINE]
Free PMC Article

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