Protectin D1

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Protectin D1
Names
Preferred IUPAC name
(4Z,7Z,10R,11E,13E,15Z,17S,19Z)-10,17-Dihydroxydocosa-4,7,11,13,15,19-hexaenoic acid
Other names
10R,17S-Dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoate; 10R,17S-Dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid; Neuroprotectin D1
Identifiers
3D model (
JSmol
)
ChemSpider
UNII
  • InChI=1S/C22H32O4/c1-2-3-10-15-20(23)17-12-8-9-13-18-21(24)16-11-6-4-5-7-14-19-22(25)26/h3,5-13,17-18,20-21,23-24H,2,4,14-16,19H2,1H3,(H,25,26)/b7-5-,9-8+,10-3-,11-6-,17-12-,18-13+/t20-,21+/m0/s1 checkY
    Key: CRDZYJSQHCXHEG-SFVBTVKNSA-N checkY
  • O=C(O)CC\C=C/C/C=C\C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)C\C=C/CC
Properties
C22H32O4
Molar mass 360.4871 g/mol
Density 1.049 g/cm3
Boiling point 559.379 °C (1,038.882 °F; 832.529 K)
0.0069
log P 4.95
Acidity (pKa) 4.82
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Protectin D1 also known as

aliphatic acyclic alkene 22 carbons in length with two hydroxyl groups at the 10 and 17 carbon positions and one carboxylic acid group at the one carbon position.[1]

Specifically, PD1 is an endogenous stereoselective lipid mediator classified as an

autocoid protectin. Autacoids are enzymatically derived chemical mediators with distinct biological activities and molecular structures. Protectins are signaling molecules that are produced enzymatically from unsaturated fatty acids. Their molecular structure is characterized by the presence of a conjugated system of double bonds.[1] PD1, like other protectins, is produced by the oxygenation of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) and it is found in many tissues, such as the retina, the lungs and the nervous system.[2][3]

PD1 has a significant role as an anti-inflammatory, anti-apoptotic and neuroprotective molecule. Studies in Alzheimer's disease animal models, in stroke patients and in human retina pigment epithelial cells (RPE) have shown that PD1 can potentially reduce inflammation induced by oxidative stress and inhibit the pro-apoptotic signal, thereby preventing cellular degeneration.[2][3][4][5] Finally, recent studies examining the pathogenicity of influenza viruses, including the avian flu (H5N1), have suggested that PD1 can potentially halt the proliferation of the virus, thus protecting respiratory cells from lethal viral infections.[6][7]

Biosynthesis of PD1

In vivo, PD1 is mainly produced as a response to inflammatory signals and it is found in various tissues, such as the

substrate (DHA) leads to the formation of the (17S)-hydro(peroxy)-DHA intermediate. This intermediate is rapidly processed to form a 16(17)-epoxide-containing molecule, which is the second intermediate. Finally, in the third step of the pathway, enzymatic hydrolysis of the 16(17)-epoxide-containing intermediate leads to the formation of PD1.[1]

Protectin D1 (PD1) Biosynthesis

Functions of PD1

In general, PD1 in vivo exhibits a potent anti-apoptotic and anti-inflammatory activity in the tissues in which it is localized. DHA, the main PD1 precursor, is mostly found in tissues such as the retinal synapses, photoreceptors, the lungs and the brain, suggesting that these tissues are more likely to be benefited from the protecting activity of PD1.[1][2][3][4][7][8]

Activity of PD1 in the retina

RPE are essential in the survival and renewal of the photoreceptors in the retina. These cells exhibit a potent phagocytic activity that ensures the proper function of the retina. Therefore, oxidative stress can potentially damage the RPE cells and cause vision impairment. Studies in human RPE cells have suggested that the presence of oxidative stress triggering molecules, such as H2O2 causes the fragmentation of the DNA that in turn triggers apoptosis.[2] These studies have proposed that PD1 acts as a signaling molecule and through its ligand-receptor interaction down-regulates the expression of genes, such as the transcription factor NF-κB. The inhibition of NF-κB results in the down-regulation of the pro-inflammatory gene COX-2 (cyclooxygenase-2) which is responsible for the release of prostaglandins, a potent pro-inflammatory mediator.[2] In addition, PD1 has an important role in regulating the expression of the Bcl-2 family proteins (Bcl-2, Bcl-xL, Bax and Bad) that precedes the release of the cytochrome c complex from the mitochondria and the formation of the apoptosome.[2][3][4] The presence of PD1 up-regulates the expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, while it inhibits the expression of the pro-apoptotic proteins Bax and Bad.[2] Specifically, PD1 regulates this protein family by promoting the dephosphorylation of Bcl-xL by protein phosphatase 2A (PP2A) at residue Ser-62 which in turn heterodimerizes with the pro-apoptotic protein Bax and inactivates it.[4] Consequently, the activity of the Bcl-2 family proteins results in the inhibition of the caspase 3 enzyme, thus preventing apoptosis and promoting RPE cell survival.[2][4]

Effects of PD1 in Alzheimer's disease

Among others,

neuronal glial cells (HNG) has been shown to trigger the down-regulation of βΑPP, thus decreasing the Aβ42 content in neuronal tissues and reducing inflammation and apoptosis.[5] Specifically, PD1 in Alzheimer's disease models has been shown to respond to the increased concentration of the pro-inflammatory molecule Aβ42 by binding and activating the peroxisome proliferator-activated receptor gamma (PPARγ) either directly or via other mechanisms. According to some models the activation of PPARγ leads to increased ubiquitination and degradation of βAPP, thus reducing the release of Aβ42.[5] Furthermore, PD1 inhibits the production of Aβ42 peptide by down-regulating β-secretase-1 (BACE1), while up-regulating the α-secretase ADAM10 and the secreted amyloid precursor protein-α (sAPPα). Overall, the above mechanism leads to the cleavage of βAPP protein though a non-amyloidogenic pathway that halts the formation of Aβ42 and prevents the premature neuronal degeneration.[5][9]

Antiviral activity of PD1

Studies in cultured human lung epithelial cells infected with the influenza virus H1N1 or H5N1 have found that endogenous production of PD1 decreases dramatically during infection due to the inhibition of 15-LO-1.[6][7] Furthermore, the same studies have shown that in vivo administration of PD1 to H1N1 infected mice can potentially inhibit both the proliferation of the virus and the inflammation caused by the infection, thus increasing survival. PD1 protects against viral infections by disrupting the virus life cycle. Specifically, PD1 inhibits the binding of viral RNA to specific nuclear export factors in the host cells, thus blocking the export of viral RNA from the nucleus to the cytosol.[6][7] The nuclear RNA export factor 1(NXF1) is of particular interest in the attenuation of viral infections via the activity of PD1. Specifically, the NXF1 transporter through its middle and C-terminal domains binds to the phenylalanine/glycine repeats in the nucleoporins (Nups) that line the nuclear pore.[7] In the absence of PD1, influenza viral RNA binds to the NXF1 transporter that later binds specifically to Nup62 nucleoporin and exports the viral RNA into the cytosol. However, the administration of PD1 has shown that this lipid mediator specifically inhibits the binding of the viral RNA to NXF1, thus disrupting the proliferation of the virus.[7]

Laboratory Synthesis of PD1

The large scale industrial production of PD1 is of great interest for pharmaceutical companies in order to harvest the potent anti-inflammatory and anti-apoptotic activities of this lipid mediator. So far, very few stereoselective laboratory syntheses of PD1 have been reported, but with a relatively low yield.[10][11]

Convergent Stereoselective Synthesis

According to one method, PD1 is synthesized in 15% yield through an 8-step

work-up with NaH2PO4 (aq.) in order to produce PD1.[10]

Convergent Stereoselective Synthesis of PD1

Alternative Stereoselective Synthesis

Alternatively, PD1 laboratory synthesis proceeds through a different stereoselective method.[11] Initially, hydroboration of a TBS-protected acetylene with Sia2BH produces a TBS-protected vinylborane. The TBS-protected vinylborane reacts with vinyliodide in the presence of a Pd-catalyst, sodium hydroxide (NaOH) and THF to produce a TBS-protected alcohol. Later treatment of the TBS-protected alcohol with TBAF removes the protecting group and produces a diol. Finally, the diol is hydrolyzed with LiOH in THF (aq.) to produce PD1.[11]

Laboratory synthesis of Protectin D1 (PD1)

Other PDs

22-hydroxy-NPD1

22-hydroxy-PD1 (22-OH-PD1; i.e. 10R,17S,20-trihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid) is an

5-oxo-eicosatetraenoic acid (i.e. 5-oxo-ETE) results in a ~100-fold fall in their activity, the omega oxidized product of PD1 has been shown to possess potent ease exhibits potent anti-inflammatory and proresolving actions by inhibiting PMN chemotaxis in vivo and in vitro and decreased pro-inflammatory mediator levels in inflammatory exudates of an animal model at levels comparable to PD1.[12][13]

Protectin DX

Protectin DX (PDX; i.e. 10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid) is the 13Z,15E,19Z isomer of NPD1 (which has the 13E,15Z,19Z double bond configuration)(see

prostaglandins; it also inhibits the platelet-aggregating action of thromboxane A2 thereby blocking the platelet aggregations responses to agents that depend on platelets to release thromboxane A2.[16]

Aspirin-triggered PD1

Aspirin-triggered PD1 (AT-PD1 or 17-epi-PD1: i.e. 10R,17R-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid) is the 10R-hydroxy isomer of PD1 (which has the 10S hydroxy residue) (see

neutrophils into the peritoneum in a mouse model of inflammatory disease; b) stimulate the Efferocytosis (i.e. engulfment and removal) of neutrophils; and c) reduce brain infarction and stroke in a rodent model.[17]

10-epi-PD1

10-Epi-PD1 (ent-AT-NPD1: i.e. 10S,17S-Dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid) is the 10S-hydroxy isomer of AT-PD1 (which has a 10R-hydroxy residue) (see

specialized proresolving mediators#Protectins/neuroprotectins). 10-Epi-PD1 was detected in only a small amount in human PMN extracts but was more potent than PD1 or PDX in blocking the inflammatory response to zymosan A-induced murine acute peritonitis.[13]

References

  1. ^
    PMID 16216871
    .
  2. ^
    PMID 15152078
    .
  3. ^
    PMID 19403949
    .
  4. ^
    PMID 20363734
    .
  5. ^
    PMID 21246057
    .
  6. ^
    PMID 23827671
    .
  7. ^
    PMID 23477864
    .
  8. PMID 16424216
    .
  9. ^
    PMID 16472763
    .
  10. ^
    PMID 24253202
    .
  11. ^
    doi:10.1016/j.tetlet.2011.03.152
    .
  12. PMID 25247845
    .
  13. ^
    PMID 26545300
    .
  14. PMID 24262603
    .
  15. S2CID 28347830
    .
  16. PMID 25223888
    .
  17. PMID 25139562
    .

External links
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