Spantide I
目录号 : GC11280
Spantide I是一种与P物质（SP）类似的具有选择性的NK1受体拮抗剂，其对NK1和NK2受体的Ki值分别为230nM和8150nM。
Cas No.:91224-37-2
Sample solution is provided at 25 µL, 10mM.
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Spantide I is an analogue of substance P (SP) and a selective NK1 receptor antagonist with Ki values of 230nM and 8150nM for NK1 and NK2 receptor, respectively [1]. The NK1 is broadly expressed in the eye, in both ocular and non-ocular cells, such as leukocytes and neurons [2]. Spantide I provides an approach to reduce type 1 and enhance the type 2 cytokine IL-10 in the infected cornea, leading to a significant reduction in corneal perforation [3].
In vitro, Spantide I (10μM) treatment of regulatory T cells (Tregs) for 48 hours reversed the reduction in Foxp3, CTLA-4, and PD-1 expression levels caused by SP treatment. At the same time, Spantide I blocked the SP signal transduction and inhibited the decrease in TGF-β levels observed in SP-induced Tregs cells [4]. Treating TG neurons isolated from dry eye disease (DED) mice with a culture medium containing Spantide I (2μM) for 24 hours significantly reduced the proliferation of vascular endothelial cells (VEC) co-cultured with the TG neurons, and also eliminated the promotion of tube formation by the VECs [5].
In vivo, treating mice with Spantide I (36μg/mouse/day; i.p.) for 7 days significantly reduced the number of corneal perforations, bacterial count, and neutrophil count in mice infected with Pseudomonas aeruginosa, and also downregulated the mRNA levels of type I cytokines (such as IFN-γ) as well as MIP-2, IL-6, TNF-α, and IL-1β [3]. Treating mice exposed to UVR-B with Spantide I (72μg/mouse/day; i.p.) for 7 days significantly reduced the expression of NKR-1 in the corneas. Spantide I has a protective effect after corneal injury induction [6].
References:
[1] Zubrzycka M, Janecka A, Traczyk WZ. Comparison of antagonistic properties of substance P analogs, spantide I, II and III, on evoked tongue jerks in rats. Endocr Regul. 2000 Mar;34(1):13-8.
[2] Demirsoy I H, Ferrari G. The NK-1 receptor signaling: distribution and functional relevance in the eye[J]. Receptors, 2022, 1(1): 98-111.
[3] Hazlett LD, McClellan SA, Barrett RP, Liu J, Zhang Y, Lighvani S. Spantide I decreases type I cytokines, enhances IL-10, and reduces corneal perforation in susceptible mice after Pseudomonas aeruginosa infection. Invest Ophthalmol Vis Sci. 2007 Feb;48(2):797-807.
[4] Taketani Y, Marmalidou A, Dohlman TH, et al. Restoration of Regulatory T-Cell Function in Dry Eye Disease by Antagonizing Substance P/Neurokinin-1 Receptor. Am J Pathol. 2020;190(9):1859-1866.
[5] Liu L, Dana R, Yin J. Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling. FASEB J. 2020;34(5):6229-6243.
[6] Gross J, Wegener AR, Kronschläger M, Schönfeld CL, Holz FG, Meyer LM. UVR-B-induced NKR-1 Expression in Ocular Tissues is blocked by Substance P Receptor Antagonist Fosaprepitant in the Exposed as well as Unexposed Partner Eye. Ocul Immunol Inflamm. 2021;29(5):963-975.
Spantide I是一种与P物质（SP）类似的具有选择性的NK1受体拮抗剂，其对NK1和NK2受体的Ki值分别为230nM和8150nM [1]。NK1R在眼睛中广泛分布，存在于眼部细胞以及非眼部细胞中，例如白细胞和神经元 [2]。Spantide I为降低感染角膜中的类型1细胞因子并增强类型2细胞因子IL-10提供了一种方法，从而显著减少了角膜穿孔的发生 [3]。
在体外，Spantide I（10μM）处理调节性T细胞（Tregs）48小时，逆转了SP处理的细胞中Foxp3、CTLA-4和PD-1表达水平的降低。同时，Spantide I阻断SP信号传导抑制了SP诱导的Tregs细胞中TGF-β水平的减少 [4]。用含Spantide I（2μM）的培养基处理从干眼症（DED ）小鼠分离的TG神经元24小时，显著降低了与TG神经元共培养的血管内皮细胞（VEC）增殖，也消除了对VEC管形成的促进 [5] 。
在体内，通过Spantide I（36μg/只/天；i.p.）治疗7天，显著减少了感染铜绿假单胞菌的小鼠角膜穿孔的数量、细菌数量以及中性粒细胞的数量，并且还下调了I型细胞因子（如IFN-γ）以及MIP-2、IL-6、TNF-α和IL-1β的mRNA水平 [3]。通过Spantide I（72μg/只/天；i.p.）治疗7天，显著减少了暴露于UVR-B小鼠角膜中NKR-1的表达。Spantide I在角膜诱导损伤后具有保护作用 [6]。
| Cell experiment [1]: | |
Cell lines | Tregs |
Preparation Method | The submandibular and cervical DLNs were harvested from normal and DED mice, and single-cell suspensions were prepared as previously described. CD4CD25 Tregs were isolated by magnetic separation using a Treg isolation kit. The purity of sorted cells (>95% Foxp3 Tregs) was confirmed by using flow cytometry analysis. Tregs were resuspended in RPMI 1640–based complete medium at a concentration of 1 × 106 cells/mL. Subsequently, 100μL of cell suspension was plated in each well of a 96-well plate. SP (1μM), Spantide I (10μM), or both were added to the Treg cultures. After 48 hours of incubation, cells were collected for flow cytometry analysis. The inhibitory function of the cultured Tregs was evaluated using the Treg inhibition assay. |
Reaction Conditions | 10μM; 48h |
Applications | Under the presence of SP, the in vitro culture of normal Tregs led to a significant decrease in the frequency of Tregs and their inhibitory function. The NK-1R antagonist Spantide I reversed the reduction in the expression levels of Foxp3, CTLA-4 and PD-1 in Tregs treated with SP. At the same time, Spantide I blocked the signal transduction of SP and inhibited the reduction in TGF-β production by SP-induced Tregs. |
| Animal experiment [2]: | |
Animal models | C57BL/6 mice |
Preparation Method | Copper-green Pseudomonas bacteria were used to infect B6 mice. On the -1st day and the 0th day (the day of infection), 36μg/mouse of synthetic Spantide I was injected intraperitoneally, and this injection was repeated daily within 5 days after infection. Control mice were similarly injected with vehicle (PBS <0.05EU/mL endotoxin). Infected corneas were collected at 1, 3, and 5 days pi for real-time PCR detection of mRNA levels of cytokines. Normal, uninfected corneas also were harvested to determine basal levels of the target cytokines. In separate experiments, infected corneas (n = 5/group/time/assay) were harvested at 3 and 5 days pi and used for ELISA analysis, viable bacterial enumeration, and MPO quantitation. |
Dosage form | 36μg/mouse/d for 7 days; i.p. |
Applications | At 3 and 5 days pi, Spantide I-treated mice had significantly less severe ocular disease than did the PBS-treated mice. Contained significantly fewer PMNs than the corneas of PBS-treated mice at 3 and 5 days pi. Significantly reduced levels of corneal TNF-α mRNA at 3 and 5 days pi. Significantly reduced the level of IL-18 mRNA at 1 day pi. |
References: | |
| Cas No. | 91224-37-2 | SDF | |
| 化学名 | (S,Z)-N'1-((2R,3Z,5S,6Z,8R,9Z,11S,12Z,14S)-8-((1H-indol-3-yl)methyl)-5-benzyl-3,6,9,12-tetrahydroxy-14-(hydroxy(imino)methyl)-1-(1H-indol-3-yl)-11-isobutyl-16-methyl-4,7,10,13-tetraazaheptadeca-3,6,9,12-tetraen-2-yl)-2-((Z)-((S)-2-((Z)-(((S)-1-((S)-6-amin | ||
| Canonical SMILES | CC(C[C@@](/N=C(O)/[C@](/N=C(O)/[C@@](/N=C(O)/[C@](/N=C(O)/[C@@](/N=C(O)/[C@](/N=C(O)/[C@](/N=C(O)/[C@]1([H])CCCN1C([C@](/N=C(O)/[C@]2([H])CCCN2C([C@@](N)([H])CCCNC(N)=N)=O)([H])CCCCN)=O)([H])CCC(O)=N)([H])CCC(O)=N)([H])CC3=CNC4=CC=CC=C34)([H])CC5=CC=CC=C5 | ||
| 分子式 | C75H108N20O13 | 分子量 | 1497.79 |
| 溶解度 | Soluble to 1 mg/ml in Water | 储存条件 | Desiccate at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.6677 mL | 3.3383 mL | 6.6765 mL |
| 5 mM | 0.1335 mL | 0.6677 mL | 1.3353 mL |
| 10 mM | 0.0668 mL | 0.3338 mL | 0.6677 mL |
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- Purity: >98.00%
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