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Pam3CSK4 (Synonyms: Pam3Cys-Ser-(Lys)4)

カタログ番号GC10273

Pam3CSK4(Pam3CysSerLys4)は、合成トリアシル化リポペプチド(LP)であり、EC50が0.47 ng/mLのTLR2 / TLR1リガンド/アゴニストです。

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Pam3CSK4 化学構造

Cas No.: 112208-00-1

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Sample solution is provided at 25 µL, 10mM.

Product has been cited by 1 publications

Product Documents

Quality Control & SDS

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Protocol

Cell experiment [1]:

Cell lines

HepaRG cell

Preparation Method

Indicated differentiated HepaRG cell lines were infected with HBV with 100 vge/cell. At day-7 post-infection , cells were treated twice with either Pam3CSK4 (100 ng/mL), IFNα (500 IU/mL), RG7834 (0.1 μM), or the nucleoside analogue lamivudine (3 TC; 1 μM) for a total exposure time of 6 days. Cells and supernatants were harvested for analyses at day-13 post-infection.

Reaction Conditions

100 ng/mL; 6 days

Applications

Pam3CSK4 was capable to inhibit HBV (genotype D) replication in dHepaRG cells. The levels of all HBV parameters analyzed, (including intracellular total HBV RNAs, viremia, and secretion of viral antigens) were significantly reduced even at very low concentration of Pam3CSK4. Pam3CSK4 was also capable to inhibit the replication of another HBV genotype (genotype C). thus suggesting a broad antiviral activity against HBV. Pam3CSK4 as a TLR2 agonist, is a potent anti-HBV agents. Pam3CSK4 inhibits RNA accumulation by both impairing HBV transcription and RNA stability. Pam3CSK4 decreases also cccDNA level via a FEN-1-dependent mechanism.

Animal experiment [2]:

Animal models

C57 BL/6 mice

Preparation Method

To analyse the influence of TLR2 heterodimer activation on IL-13-induced itch-like behaviour, C57 BL/6 mice were pre-administered with Pam3CSK4 (20 μg/100 μl sterilized water) by gavage every three days for 3 times . In another experiment, FSL-1 (0.3 mg/kg, 60 μl sterilized water) was intraperitoneally injected 14 h before IL-13 injection. Control mice were given sterilized water only. All of these mice were then intradermally injected with IL-13 (1 μg/10 μl) or vehicle into the left cheek. All the mice were video-recorded for 1 h for the analysis of scratching bouts.

Dosage form

Pam3CSK4 (20 μg/100 μl sterilized water) by gavage every three days for 3 times

Applications

As a cutaneous regulator, IL-13 activates sensory neurons and participates in the initiation of AD and itch. Pam3CSK4 enhances IL-13-induced calcium transient in sensory neurons and elevates IL-13-induced Itch-like behaviours in mice。

References:

[1]. Desmares M, Delphin M,et,al. Insights on the antiviral mechanisms of action of the TLR1/2 agonist Pam3CSK4 in hepatitis B virus (HBV)-infected hepatocytes. Antiviral Res. 2022 Aug 10;206:105386. doi: 10.1016/j.antiviral.2022.105386. Epub ahead of print. PMID: 35963549.

[2]. Xiao S, Lu Z, et,al. Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis. Brain Behav Immun. 2021 Nov;98:28-39. doi: 10.1016/j.bbi.2021.08.211. Epub 2021 Aug 13. PMID: 34391816.

Background

Pam3CSK4(Pam3CysSerLys4)は、合成トリアシル化リポペプチド(LP)であり、TLR2 / TLR1リガンドアゴニストであり、EC50は0.47 ng/mLです [10] 。 Pam3CSK4は、細菌のLPのアシル化されたアミノ末端を模倣しています。細菌のLPはグラム陽性およびグラム陰性細菌に見られる炎症性細胞壁成分の家族です。これらの細菌LPはTLR2によって認識されます。 TLR2は様々な病原体関連分子パターン(PAMP)を検出する上で重要な役割を果たす受容体です。 トリアシル化LPであるPam3CSK4の認識は、TLR2が介在し、そのサイトプラズマ領域がTLR1と協力してNF-κB活性化につながる信号伝達カスケードを引き起こします [1]

HepaRG細胞では、Pam3CSK4はHBVに対して広範な抗ウイルス活性を示します。 Pam3CSK4は、よく特徴化された特異的なTLR1 / 2リガンドです[2]。 Pam4CSK4の抗HBV効果はTLR1 / 2およびそのアダプターであるMyD88に依存し、特定のsiRNAを用いてTLR1またはTLR6を標的とすることがPam3CSK4活性化の文脈でTLR2のフィードフォワード発現に影響するが、TLR1無効化はPam3CSK4の抑制効果を減少させました。 TLR2の低い機能レベルでも、Pam3CSK4の治療効果を生み出す十分なものでした[4,5]。これにより、Pam3CSK4が肝細胞内でおそらくTLR1 / 2ヘテロ二量体を介してシグナル伝達することが確認されました[3]。

Pam3CSK4によるTLR2/1ヘテロ二量体の活性化は痛みとかゆみを引き起こし、リポテイコ酸(LTA)や酵母グリカンによるTLR2/6ヘテロ二量体の活性化はかゆみを引き起こします[9]。皮膚調節因子であるIL-13は感覚神経細胞を活性化し、ADおよびかゆみの開始に参加します[7]。IL-13単独では掻痒数の有意な増加が見られませんが、TLR2は感覚神経細胞でIL-13シグナル伝達を促進します。先天的なTLR2シグナル伝達は、一過性TH2細胞介在性皮膚炎を持続的な炎症に変換し、これが慢性的な人間のADと関連しています[8]。Pam3CSK4で前処置されたマウスでは、IL-13注射後に車両注射と比べて約2倍多く掻く行動が見られました[6]。Pam3CSK4は感覚神経細胞内でIL-13誘発カルシウムトランジェントを増強し、マウスにおけるIL-13誘発かゆみ様行動を高めます。

References:
[1]: Ozinsky A, Underhill DM, et,al.The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13766-71. doi: 10.1073/pnas.250476497. PMID: 11095740; PMCID: PMC17650.
[2]: Lucifora J, Xia Y, et,al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 2014 Mar 14;343(6176):1221-8. doi: 10.1126/science.1243462. Epub 2014 Feb 20. PMID: 24557838; PMCID: PMC6309542.
[3]: K. Visvanathan, N.A. Skinner, et al. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology. doi:10.1002. 2006.
[4]: Xiao S, Lu Z, et,al. Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis. Brain Behav Immun. 2021 Nov;98:28-39. doi: 10.1016/j.bbi.2021.08.211. Epub 2021 Aug 13. PMID: 34391816.
[5]: Erickson S, Heul AV, et,al. New and emerging treatments for inflammatory itch. Ann Allergy Asthma Immunol. 2021 Jan;126(1):13-20. doi: 10.1016/j.anai.2020.05.028. Epub 2020 Jun 1. PMID: 32497711.
[6]: Oetjen LK, Mack MR, et,al. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell. 2017 Sep 21;171(1):217-228.e13. doi: 10.1016/j.cell.2017.08.006. Epub 2017 Sep 7. PMID: 28890086; PMCID: PMC5658016.
[7]: Kaesler S, Volz T, et,al. Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10. J Allergy Clin Immunol. 2014 Jul;134(1):92-9. doi: 10.1016/j.jaci.2014.02.017. Epub 2014 Apr 1. PMID: 24698321.
[8]: Liu T, Gao YJ, et,al. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull. 2012 Apr;28(2):131-44. doi: 10.1007/s12264-012-1219-5. PMID: 22466124; PMCID: PMC3347759.
[9]:Wang TT, Xu XY, et,al. Activation of Different Heterodimers of TLR2 Distinctly Mediates Pain and Itch. Neuroscience. 2020 Mar 1;429:245-255. doi: 10.1016/j.neuroscience.2020.01.010. Epub 2020 Jan 16. PMID: 31954829.
[10]:Irvine KL, Hopkins LJ, Gangloff M, Bryant CE. The molecular basis for recognition of bacterial ligands at equine TLR2, TLR1 and TLR6. Vet Res. 2013 Jul 4;44(1):50. doi: 10.1186/1297-9716-44-50. PMID: 23826682; PMCID: PMC3716717.

Chemical Properties

Cas No. 112208-00-1 SDF
同義語 Pam3Cys-Ser-(Lys)4
Chemical Name (2S,3Z,5S,6Z,8S,9Z,11S,12Z,14S,15Z,17R)-2,5,8,11-tetrakis(4-aminobutyl)-4,7,10,13,16-pentahydroxy-17-((Z)-(1-hydroxyhexadecylidene)amino)-14-(hydroxymethyl)-24-oxo-21-(palmitoyloxy)-23-oxa-19-thia-3,6,9,12,15-pentaazanonatriaconta-3,6,9,12,15-pentaen-1-oi
Canonical SMILES CCCCCCCCCCCCCCC/C(O)=N/[C@@](/C(O)=N/[C@@](/C(O)=N/[C@@](/C(O)=N/[C@@](/C(O)=N/[C@@](/C(O)=N/[C@@](C(O)=O)([H])CCCCN)([H])CCCCN)([H])CCCCN)([H])CCCCN)([H])CO)([H])CSCC(OC(CCCCCCCCCCCCCCC)=O)([H])COC(CCCCCCCCCCCCCCC)=O
Formula C81H156N10O13S M.Wt 1510.24
溶解度 50 mg/mL in DMSO ( Need ultrasonic); 16.67 mg/mL in Water ( Needultrasonic) Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

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1 mg 5 mg 10 mg
1 mM 0.6621 mL 3.3107 mL 6.6215 mL
5 mM 0.1324 mL 0.6621 mL 1.3243 mL
10 mM 0.0662 mL 0.3311 mL 0.6621 mL
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Average Rating: 5 ★★★★★ (Based on Reviews and 38 reference(s) in Google Scholar.)

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