PAP-1
(Synonyms: 4-(4-苯氧基丁氧基)-7H-呋喃并[3,2-G][1]苯并吡喃-7-酮,5-(4-Phenoxybutoxy)psoralen) 目录号 : GC36849
An inhibitor of Kv1.3 channels
Cas No.:870653-45-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
PAP-1 is an inhibitor of Kv1.3 voltage-gated potassium channels (EC50 = 2 nM at -80 mV in cells overexpressing the human channel).1 It is selective for Kv1.3 over a panel of 22 ion channels, including potassium, sodium, calcium, and chloride channels (EC50s = 45-15,000 nM for all). PAP-1 inhibits anti-CD3 antibody-induced proliferation of isolated human CCR7- effector memory T cells. In vivo, PAP-1 (3 mg/kg) inhibits ovalbumin-induced delayed-type hypersensitivity in rats.
1.Schmitz, A., Sankaranarayanan, A., Azam, P., et al.Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseasesMol. Pharmacol.68(5)1254-1270(2005)
| Cas No. | 870653-45-5 | SDF | |
| 别名 | 4-(4-苯氧基丁氧基)-7H-呋喃并[3,2-G][1]苯并吡喃-7-酮,5-(4-Phenoxybutoxy)psoralen | ||
| Canonical SMILES | O=C1C=CC(C(O1)=CC2=C3C=CO2)=C3OCCCCOC4=CC=CC=C4 | ||
| 分子式 | C21H18O5 | 分子量 | 350.36 |
| 溶解度 | DMSO: 50 mg/mL (142.71 mM); Water: < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.8542 mL | 14.271 mL | 28.5421 mL |
| 5 mM | 0.5708 mL | 2.8542 mL | 5.7084 mL |
| 10 mM | 0.2854 mL | 1.4271 mL | 2.8542 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
PAP-1 ameliorates DSS-induced colitis with involvement of NLRP3 inflammasome pathway
Int Immunopharmacol 2019 Oct;75:105776.PMID:31351364DOI:10.1016/j.intimp.2019.105776.
Background: Macrophages are a primary type of innate immune cells activated in colitis. Kv1.3 channel is one of the major potassium channels in macrophages. NLRP3 inflammasome is a downstream molecule of Kv1.3 channel. PAP-1, a specific Kv1.3 channel blocker, has been shown to have immune-regulatory effects. Objective: To investigate the effect of PAP-1 on intestinal inflammation in DSS-induced colitis and explore its possible mechanism. Methods: C57BL/6 mice were divided into four groups: normal control group, normal+PAP-1 injection group, DSS model group, DSS model+PAP-1 injection group. Experimental colitis was induced by 5% DSS treatment; mice were injected intraperitoneally with PAP-1 from the first day for 7 consecutive days; then all mice were sacrificed, followed by isolation of colon tissue, peritoneal macrophages and spleen macrophages. The anti-inflammatory effects of PAP-1 and the expression levels of Kv1.3, iNOS, pro-IL-1β, IL-1β and NLRP3 inflammasome were measured. Results: PAP-1 reduced DSS-induced colonic pathological damage, DAI score, MPO activity and levels of IL-1, IL-6, TNF-a, IL-18. Compared with the DSS model group, the expression of Kv1.3, iNOS, NLRP3, ASC, caspase-1p20, pro-IL-1β and IL-1β in colon were decreased in the DSS-induced colitis mice with PAP-1 injection. PAP-1 also reduced the expression of Kv1.3, iNOS, NLRP3, caspase-1p20 and IL-1β on macrophages in colitis mice. Conclusion: PAP-1 had protective effects on DSS-induced colitis, which might be ascribed to the regulation of NLRP3 inflammasome pathway. Therefore, we found that PAP-1 was useful as a therapeutic agent in IBD and suggested a potential important role of PAP-1 in NLRP3 inflammasome-associated diseases.
Bergamottin and PAP-1 Induced ACE2 Degradation to Alleviate Infection of SARS-CoV-2
Int J Mol Sci 2022 Oct 19;23(20):12565.PMID:36293419DOI:10.3390/ijms232012565.
Angiotensin-converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. However, inhibitors such as PAP-1 and bergamottin have been discovered; both of them can preferentially bind to ACE2, prevent RBD Spike S protein from binding to ACE2, and reduce the binding sites for RBD Spike S protein. In addition, we investigated the binding energy of PAP-1 and bergamottin with ACE2 through molecular docking with bio-layer interferometry (BLI) and found relatively high binding affinity (KD = 48.5 nM, 53.1 nM) between the PAP-1 and bergamottin groups. In addition, the nanomolar fraction had no effect on growth of the AT-II cell, but 150 µM PAP-1 and 75 µM bergamottin inhibited the proliferation of AT-II cells in vitro by 75% and 68%, respectively. Meanwhile, they significantly reduced ACE2 mRNA and proteins by 67%, 58% and 55%, 41%, respectively. These results indicate that psoralen compounds PAP-1 and bergamottin binding to ACE2 protein could be further developed in the fight against COVID-19 infection during the current pandemic. However, attention should be paid to the damage to human alveolar type II epithelial cells.
Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson's disease
J Clin Invest 2020 Aug 3;130(8):4195-4212.PMID:32597830DOI:10.1172/JCI136174.
Characterization of the key cellular targets contributing to sustained microglial activation in neurodegenerative diseases, including Parkinson's disease (PD), and optimal modulation of these targets can provide potential treatments to halt disease progression. Here, we demonstrated that microglial Kv1.3, a voltage-gated potassium channel, was transcriptionally upregulated in response to aggregated α-synuclein (αSynAgg) stimulation in primary microglial cultures and animal models of PD, as well as in postmortem human PD brains. Patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translated to increased Kv1.3 channel activity. The kinase Fyn, a risk factor for PD, modulated transcriptional upregulation and posttranslational modification of microglial Kv1.3. Multiple state-of-the-art analyses, including Duolink proximity ligation assay imaging, revealed that Fyn directly bound to Kv1.3 and posttranslationally modified its channel activity. Furthermore, we demonstrated the functional relevance of Kv1.3 in augmenting the neuroinflammatory response by using Kv1.3-KO primary microglia and the Kv1.3-specific small-molecule inhibitor PAP-1, thus highlighting the importance of Kv1.3 in neuroinflammation. Administration of PAP-1 significantly inhibited neurodegeneration and neuroinflammation in multiple animal models of PD. Collectively, our results imply that Fyn-dependent regulation of Kv1.3 channels plays an obligatory role in accentuating the neuroinflammatory response in PD and identify Kv1.3 as a potential therapeutic target for PD.
PAP-1, the mutated gene underlying the RP9 form of dominant retinitis pigmentosa, is a splicing factor
Exp Cell Res 2004 Nov 1;300(2):283-96.PMID:15474994DOI:10.1016/j.yexcr.2004.07.029.
PAP-1 is an in vitro phosphorylation target of the Pim-1 oncogene. Although PAP-1 binds to Pim-1, it is not a substrate for phosphorylation by Pim-1 in vivo. PAP-1 has recently been implicated as the defective gene in RP9, one type of autosomal dominant retinitis pigmentosa (adRP). However, RP9 is a rare disease and only two missense mutations have been described, so the report of a link between PAP-1 and RP9 was tentative. The precise cellular role of PAP-1 was also unknown at that time. We now report that PAP-1 localizes in nuclear speckles containing the splicing factor SC35 and interacts directly with another splicing factor, U2AF35. Furthermore, we used in vitro and in vivo splicing assays to show that PAP-1 has an activity, which alters the pattern of pre-mRNA splicing and that this activity is dependent on the phosphorylation state of PAP-1. We used the same splicing assay to examine the activities of two mutant forms of PAP-1 found in RP9 patients. The results showed that while one of the mutations, H137L, had no effect on splicing activity compared with that of wild-type PAP-1, the other, D170G, resulted in both a defect in splicing activity and a decreased proportion of phosphorylated PAP-1. The D170G mutation may therefore cause RP by altering splicing of retinal genes through a decrease in PAP-1 phosphorylation. These results demonstrate that PAP-1 has a role in pre-mRNA splicing and, given that three other splicing factors have been implicated in adRP, this finding provides compelling further evidence that PAP-1 is indeed the RP9 gene.
PAP-1, a novel target protein of phosphorylation by pim-1 kinase
Eur J Biochem 2000 Aug;267(16):5168-78.PMID:10931201DOI:10.1046/j.1432-1327.2000.01585.x.
Protooncogene, pim-1, has been reported to be a predisposition for lymphomagenesis along with myc, and its protein product, Pim-1, has been shown to be a serine/threonine protein kinase, whose activity is involved in proliferation and differentiation of blood cells. The signal transduction pathways neither to nor from Pim-1, however, have been clarified. We have cloned a cDNA encoding a novel Pim-1 binding protein, PAP-1, comprising 213 amino acids with a basic amino-acid cluster near the C-terminus. PAP-1 was colocalized with Pim-1 in human HeLa cell nuclei. The in vitro binding assays using GST fusion proteins of the wild-type and various deletion mutants revealed that the whole molecule of Pim-1 is required for the binding activity to PAP-1 and that Pim-1 binds to the region from amino-acid numbers 1-147 of PAP-1, or to two segments in the region. The association of PAP-1 with Pim-1 was also shown in vivo in transfected cells. Furthermore, PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase.