Structural analogs of pulmonary surfactant phosphatidylglycerol inhibit toll-like receptor 2 and 4 signaling

Abstract

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.

Tandem mass spectrometry of novel ether‐linked phospholipid analogs of anionic pulmonary surfactant phospholipids

“…Lung alveoli are the only tissue location where PG is found abundantly in humans, reaching concentrations between 5 and 10 mg/mL . Recent studies have demonstrated that PG is an important regulator of the innate antiviral defense and inflammation …”

“…The molecule 1‐palmitoyl‐2‐oleoyl‐ sn ‐glycero‐3‐phosphoglycerol (PG(16:0/18:1)) has been previously found to have potent antiviral activity against respiratory syncytial virus and influenza A . PG(16:0/18:1) also suppressed inflammation by antagonizing multiple toll‐like receptors . The biological activity of PG(16:0/18:1) has prompted studies to explore structure/function relationships of structurally related molecules that might surpass PG(16:0/18:1) in efficacy, potency and biological half‐life .…”

“…[4] Recent studies have demonstrated that PG is an important regulator of the innate antiviral defense and inflammation. [5][6][7][8][9][10] The molecule 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (PG(16:0/18:1)) has been previously found to have potent antiviral activity against respiratory syncytial virus and influenza A. [5,[7][8][9] PG(16:0/18:1) also suppressed inflammation by antagonizing multiple toll-like receptors.…”

“…[5,[7][8][9] PG(16:0/18:1) also suppressed inflammation by antagonizing multiple toll-like receptors. [6,10,11] The biological activity of PG(16:0/18:1) has prompted studies to explore structure/function relationships of structurally related molecules that might surpass PG (16:0/18:1) in efficacy, potency and biological half-life. [10] This led to the synthesis of novel phospholipid analogs of PG(16:0/ 18:1) with a xylitol head group which we have termed phosphatidyl xylitol (PX).…”

“…[6,10,11] The biological activity of PG(16:0/18:1) has prompted studies to explore structure/function relationships of structurally related molecules that might surpass PG (16:0/18:1) in efficacy, potency and biological half-life. [10] This led to the synthesis of novel phospholipid analogs of PG(16:0/ 18:1) with a xylitol head group which we have termed phosphatidyl xylitol (PX). [12] Xylitol is a five-carbon sugar alcohol approved for use by the US Food and Drug Administration as a bulk sweetener and has a similar structure to glycerol.…”