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STRUCTURAL ANALOGS OF PULMONARY SURFACTANT PHOSPHATIDYLGLYCEROL ANTAGONIZE ACTIVATION OF TOLL‐LIKE RECEPTORS 2 AND 4
Author(s) -
Kandasamy Pitchaimani,
Berry Karin A Zemski,
Leslie Christina C,
Murphy Robert C,
Voelker Dennis R
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb224
Subject(s) - chemistry , alkyl , stereochemistry , receptor , pulmonary surfactant , phosphatidylglycerol , tlr2 , phospholipid , biochemistry , tlr4 , organic chemistry , membrane , phosphatidylcholine
The pulmonary surfactant phospholipid, palmitoyloleoylphosphatidylglycerol (POPG), inhibits TLR2 and TLR4 signaling from the cell surface of macrophages. In this study we sought to develop structural analogs of POPG that vary in polar head group length, hydroxylation and alkyl branching, as novel compounds for suppressing the TLR inflammatory responses. These analogs were synthesized using a transphosphatidylation reaction. Analogs of POPG with C3 and C4 alkyl head group length (POP‐PROPANOL and POP‐BUTANOL) are less effective than POPG as TLR2 and TLR4 antagonists. However, adding a hydroxyl group at the alkyl chain 2, 3 or 4‐position (POP‐PROPANEDIOLS or POP‐BUTANEDIOLS) restored their inhibitory effects against TLR2 and TLR4 agonists. Interestingly, analogs with C1 and C2 alkyl head group length (POP‐METHANOL and POP‐ETHANOL) were effective as LPS antagonists. POP‐DIMETHYLPROPANEDIOL contains 2 methyl groups at the head group alkyl 2 position; and this analog is effective for inhibition of an LPS stimulus. However, it is a weak inhibitor of MALP‐2 induced AA release. Addition of amino group at the alkyl 2 position (POP‐SERINOL) completely abolished the potency of analogs. Collectively, these findings identify new compounds for antagonizing TLR2 and TLR4 activation and define structural properties for discriminating between the two receptor systems. NIH‐HL094629, COLORADO C2D2.