Dalazatide (SHK-186)   中文名称: 达拉扎肽

Kv1.3 potassium channel (IC₅₀ = 69 pM for human Kv1.3; >1,000-fold selectivity over related channels including Kv1.1, Kv1.4, Kv1.6, Kv1.7, KCa3.1, and hERG) [1]
KV1.3 potassium channel (IC50 = 11 pM) [1][2][3]

在 Ova 特异性 GFP+ 效应记忆 T (Tem) 细胞中，dalacazide (ShK-186) (0-1000 pM) 剂量依赖性地抑制 Kv1.3 电流，Kd 为 65 ± 5 pM[3]。达拉扎肽（0-100 nM；3 天）以剂量依赖性方式抑制 CCR7 阳性 T 细胞的增殖[3]。通过减少钙传输和阻断 β1 整合素激活，达拉扎肽（100 nM；30 分钟）将效应记忆 T (Tem) 细胞固定在炎症部位[3]。

---

Dalazatide 选择性抑制 TEM（效应记忆 T）细胞上的 Kv1.3 通道，减少钙内流及下游促炎细胞因子（如 IFN-γ、TNF-α、IL-17）的产生，从而抑制 TEM 细胞增殖与活化，且不影响初始 T 细胞或中央记忆 T 细胞 [2]

在系统性红斑狼疮（SLE）患者的 TEM 细胞中，Dalazatide 阻断了 Kv1.3 依赖性电流，降低了 TCR 刺激的钙信号传导，并抑制细胞因子（IL-2、IFN-γ）分泌 [2]

在斑块状银屑病的 1b 期临床试验（n=24）中，皮下注射 Dalazatide（0.04–0.12 mg/kg，每周两次，持续 8 周）显著降低 PASI 评分（平均改善 54%），组织学显示表皮厚度减小。皮损活检中 TEM 细胞浸润减少，角质形成细胞分化标志物恢复正常 [1]

在 DTH（迟发型超敏反应）小鼠模型中，静脉注射 Dalazatide（2 mg/kg）通过抑制 T 细胞向炎症组织迁移及减少细胞因子产生，阻断了 TEM 细胞介导的炎症。活体成像证实炎症部位 TEM 细胞运动性降低 [3]

针对 SLE 的临床前研究表明，Dalazatide 通过选择性靶向自身反应性 TEM 细胞，减轻了狼疮易感小鼠的自身抗体产生和肾脏病理损伤 [2]

细胞增殖测定 [3]
细胞类型： CCR7− T 细胞 [3]
测试浓度： 0- 100nM
孵育时间：3天
实验结果：抑制细胞增殖，IC50为180±37pM。

---

从人 PBMC 或 SLE 患者血液中分离 TEM 细胞。通过膜片钳电生理记录 Kv1.3 电流。使用 Fluo-4 AM 染料检测抗 CD3/CD28 抗体刺激 TCR 后的钙流变化 [2]

TEM 细胞活化 48 小时后，采用 ELISA 定量细胞因子（IFN-γ、TNF-α、IL-17）分泌。增殖活性通过 [³H]-胸苷掺入法评估 [2]

在 DTH 成像实验中，小鼠 TEM 细胞用 CFSE 标记并过继转移。抗原激发后，采用双光子活体显微镜追踪耳廓组织中的细胞运动性 [3]

Animal/Disease Models: Lewis rat, delayed-type dalazatide (ShK-186) (100 μg/kg; sc; Once) delays delayed-type hypersensitivity reactions in the dye and dyes the internal movement and activation of Tem cells [3] . Hypersensitivity (DTH) model [3]
Doses: 100 μg/kg
Route of Administration: One subcutaneous injection
Experimental Results: Compared with rats injected with normal saline, DTH was diminished at all time points. Inhibits the proliferation of Tem cells.

---

In DTH studies, mice received 2 mg/kg Dalazatide intravenously 1 hour before antigen challenge. Controls received peptide vehicle [3]

For psoriasis, humanized mouse models were injected subcutaneously with 0.08–0.12 mg/kg Dalazatide twice weekly. Efficacy endpoints included histopathology and PASI-like scoring [1]

Lupus-prone mice (NZB/W F1) were dosed subcutaneously with 0.1 mg/kg Dalazatide 3×/week. Kidney IgG deposits and serum autoantibodies were monitored [2]

Phase 1b data (psoriasis) showed subcutaneous Dalazatide had a half-life of ~1.3 hours and dose-proportional exposure (C_max and AUC). Bioavailability was >80% [1]

No severe adverse events in psoriasis patients. Mild injection-site reactions occurred in <10% of subjects. No changes in vital signs, ECG, or laboratory parameters [1]

In animal studies, no organ toxicity or off-target ion channel effects (e.g., cardiac hERG) at therapeutic doses [2]

[1]. Dalazatide (ShK-186), a first-in-class peptide inhibitor of Kv1. 3 potassium channels, demonstrates safety, tolerability and proof of concept of efficacy in patients with active plaque psoriasis. J. Invest. Dermatol., 2016, 136(8).

[2]. Thu0285 Dalazatide, an Inhibitor of the KV1. 3 Channel on Activated Effector Memory T Cells, Has Immunotherapy Potential in Systemic Lupus Erythematosus. 2016.

[3]. Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block. Immunity. 2008 Oct 17;29(4):602-14.

Dalazatide is a 37-amino acid peptide derived from sea anemone ShK. It treats autoimmune diseases by selectively inhibiting Kv1.3 on TEM cells, which drive chronic inflammation [1][2]

Clinical proof-of-concept established for plaque psoriasis; potential applications include SLE, rheumatoid arthritis, and multiple sclerosis [1][2]

Mechanism involves suppression of TEM cell activation without broad immunosuppression [3]

C184H296N57O55PS7

4442.09673118591

4439.993

C, 49.75; H, 6.72; N, 17.97; O, 19.81; P, 0.70; S, 5.05

1081110-69-1

Dalazatide TFA

86278334

H-{pY}-{AEEA}-Arg-Ser-Cys-Ile-Asp-Thr-Ile-Pro-Lys-Ser-Arg-Cys-Thr-Ala-Phe-Gln-Cys-Lys-His-Ser-Met-Lys-Tyr-Arg-Leu-Ser-Phe-Cys-Arg-Lys-Thr-Cys-Gly-Thr-Cys-NH2 (disulfide bridge:Cys5-Cys37,Cys14-Cys30,Cys19-Cys34)

H-{pY}-{AEEA}-RSCIDTIPKSRCTAFQCKHSMKYRLSFCRKTCGTC-NH2 (disulfide bridge:Cys5-Cys37,Cys14-Cys30,Cys19-Cys34)

White to off-white solid powder

-16.9

2020

66

73

83

304

10300

40

S1C[C@H]2C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@@H]3C(N[C@H](C(N[C@H](C(N[C@@H](CO)C(N[C@@H](CCSC)C(N[C@H](C(N[C@@H](CC4C=CC(=CC=4)O)C(N[C@@H](CCCNC(=N)N)C(N[C@@H](CC(C)C)C(N[C@@H](CO)C(N[C@@H](CC4C=CC=CC=4)C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NC(CSSC3)C(NCC(N[C@@H]([C@@H](C)O)C(N[C@H](C(N)=O)CSSC[C@@H](C(N[C@@H]([C@@H](C)CC)C(N[C@@H](CC(=O)O)C(N[C@@H]([C@@H](C)O)C(N[C@@H]([C@@H](C)CC)C(N3CCC[C@H]3C(N[C@H](C(N[C@H](C(N[C@H](C(N2)=O)CCCNC(=N)N)=O)CO)=O)CCCCN)=O)=O)=O)=O)=O)=O)NC([C@H](CO)NC([C@](CCCNC(=N)N)(N(C(C)=O)C([C@H](CC2C=CC(=CC=2)OP(=O)(O)O)N)=O)OCCOCCN)=O)=O)=O)=O)=O)=O)[C@@H](C)O)=O)CCCCN)=O)CCCNC(=N)N)=O)CS1)=O)=O)=O)=O)=O)=O)CCCCN)=O)=O)=O)CC1=CNC=N1)=O)CCCCN)=O)=O)CCC(N)=O)=O)CC1C=CC=CC=1)=O)C)=O)[C@@H](C)O)=O

GORAHSAIYZMTHZ-LBFSFEBVSA-N

InChI=1S/C184H296N57O55PS7/c1-14-94(5)139-172(283)223-124(79-138(254)255)162(273)238-144(100(11)249)176(287)236-140(95(6)15-2)178(289)240-68-33-46-135(240)171(282)217-112(41-24-28-61-187)152(263)224-125(82-242)163(274)212-116(45-32-66-204-182(197)198)153(264)229-134-91-304-303-89-132-168(279)214-114(43-30-64-202-180(193)194)148(259)210-113(42-25-29-62-188)156(267)237-143(99(10)248)175(286)232-130(147(258)206-81-137(253)234-141(97(8)246)174(285)227-129(145(192)256)86-299-301-90-133(169(280)235-139)231-166(277)128(85-245)233-179(290)184(58-34-67-205-183(199)200,295-71-70-294-69-63-189)241(101(12)250)177(288)109(190)74-104-49-53-108(54-50-104)296-297(291,292)293)87-300-302-88-131(228-154(265)117(55-56-136(191)252)215-158(269)120(75-102-35-18-16-19-36-102)218-146(257)96(7)208-173(284)142(98(9)247)239-170(134)281)167(278)213-111(40-23-27-60-186)150(261)222-123(78-106-80-201-92-207-106)161(272)226-126(83-243)164(275)216-118(57-72-298-13)155(266)209-110(39-22-26-59-185)149(260)220-122(77-105-47-51-107(251)52-48-105)159(270)211-115(44-31-65-203-181(195)196)151(262)219-119(73-93(3)4)157(268)225-127(84-244)165(276)221-121(160(271)230-132)76-103-37-20-17-21-38-103/h16-21,35-38,47-54,80,92-100,109-135,139-144,242-249,251H,14-15,22-34,39-46,55-79,81-91,185-190H2,1-13H3,(H2,191,252)(H2,192,256)(H,201,207)(H,206,258)(H,208,284)(H,209,266)(H,210,259)(H,211,270)(H,212,274)(H,213,278)(H,214,279)(H,215,269)(H,216,275)(H,217,282)(H,218,257)(H,219,262)(H,220,260)(H,221,276)(H,222,261)(H,223,283)(H,224,263)(H,225,268)(H,226,272)(H,227,285)(H,228,265)(H,229,264)(H,230,271)(H,231,277)(H,232,286)(H,233,290)(H,234,253)(H,235,280)(H,236,287)(H,237,267)(H,238,273)(H,239,281)(H,254,255)(H4,193,194,202)(H4,195,196,203)(H4,197,198,204)(H4,199,200,205)(H2,291,292,293)/t94-,95-,96-,97+,98+,99+,100+,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130?,131-,132-,133-,134-,135-,139-,140-,141-,142-,143-,144-,184+/m0/s1

2-[(1R,2aS,4S,7S,10S,13S,19S,22S,25S,28S,31R,36R,39S,48S,51S,54S,57R,60S,63S,66S,69S,72S,75S,78S,81S,84S,87S,90R,93S,96S,99S)-31-[[(2S)-2-[[(2R)-2-[acetyl-[(2S)-2-amino-3-(4-phosphonooxyphenyl)propanoyl]amino]-2-[2-(2-aminoethoxy)ethoxy]-5-carbamimidamidopentanoyl]amino]-3-hydroxypropanoyl]amino]-10,51,75,87-tetrakis(4-aminobutyl)-93-(3-amino-3-oxopropyl)-60,96-dibenzyl-19,28-bis[(2S)-butan-2-yl]-4,54,69-tris(3-carbamimidamidopropyl)-36-carbamoyl-2a,22,39,48-tetrakis[(1R)-1-hydroxyethyl]-7,63,81-tris(hydroxymethyl)-72-[(4-hydroxyphenyl)methyl]-84-(1H-imidazol-4-ylmethyl)-99-methyl-66-(2-methylpropyl)-78-(2-methylsulfanylethyl)-1a,3,4a,6,9,12,18,21,24,27,30,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98-dotriacontaoxo-6a,7a,10a,11a,33,34-hexathia-a,2,3a,5,8,11,17,20,23,26,29,37,40,43,46,49,52,55,58,61,64,67,70,73,76,79,82,85,88,91,94,97-dotriacontazatetracyclo[55.47.4.445,90.013,17]dodecahectan-25-yl]acetic acid

Dalazatide; Dalazatide [INN]; SHK-186; UNII-6U0259J807; 1081110-69-1; 6U0259J807; o-PHOSPHONO-L-Tyrosyl-2-(2-(2-aminoethoxy)ethoxy)acetyl(potassium channel toxin kappa-stichotoxin-shela stoichactis helianthus (caribbean sea anemone)) peptidamide;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

---

注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

View More

注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

---

口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

View More

口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

---

注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。