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Dalazatide (SHK-186) is a peptide-based blocker of KV1.3 channel used for treating autoimmune diseases. It is a first-in-class and investigational drug that may be used for the treatment of autoimmune diseases such as lupus erythematosus, psoriasis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, and multiple sclerosis (MS).
Physicochemical Properties
| Molecular Formula | C184H296N57O55PS7 |
| Molecular Weight | 4442.09673118591 |
| Exact Mass | 4439.993 |
| Elemental Analysis | C, 49.75; H, 6.72; N, 17.97; O, 19.81; P, 0.70; S, 5.05 |
| CAS # | 1081110-69-1 |
| Related CAS # | Dalazatide TFA |
| PubChem CID | 86278334 |
| Sequence | 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) |
| SequenceShortening | H-{pY}-{AEEA}-RSCIDTIPKSRCTAFQCKHSMKYRLSFCRKTCGTC-NH2 (disulfide bridge:Cys5-Cys37,Cys14-Cys30,Cys19-Cys34) |
| Appearance | White to off-white solid powder |
| LogP | -16.9 |
| Hydrogen Bond Donor Count | 66 |
| Hydrogen Bond Acceptor Count | 73 |
| Rotatable Bond Count | 83 |
| Heavy Atom Count | 304 |
| Complexity | 10300 |
| Defined Atom Stereocenter Count | 40 |
| SMILES | 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 |
| InChi Key | GORAHSAIYZMTHZ-LBFSFEBVSA-N |
| InChi Code | 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 |
| Chemical Name | 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 |
| Synonyms | 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; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
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] |
| ln Vitro |
In Ova-specific GFP+ effector memory T (Tem) cells, dalacazide (ShK-186) (0-1000 pM) dose-dependently inhibits the Kv1.3 current with a Kd of 65 ± 5 pM[3]. The proliferation of CCR7-positive T cells is inhibited by dalazatide (0-100 nM; 3 days) in a dose-dependent manner[3]. By reducing calcium transmission and blocking β1 integrin activation, dalazatide (100 nM; 30 min) immobilizes effector memory T (Tem) cells at inflammatory sites[3].
Dalazatide selectively inhibits Kv1.3 channels on TEM (effector memory T) cells, reducing calcium influx and downstream pro-inflammatory cytokine production (e.g., IFN-γ, TNF-α, IL-17). This inhibition suppresses TEM cell proliferation and activation without affecting naïve or central memory T cells [2] In TEM cells from SLE patients, Dalazatide blocked Kv1.3-dependent currents, reduced TCR-stimulated calcium signaling, and inhibited cytokine secretion (IL-2, IFN-γ) [2] |
| ln Vivo |
In a phase 1b trial for plaque psoriasis (n=24), subcutaneous Dalazatide (0.04–0.12 mg/kg twice weekly for 8 weeks) significantly reduced PASI scores (mean 54% improvement) and histological epidermal thickness. Lesional biopsies showed decreased TEM cell infiltrates and normalized keratinocyte differentiation markers [1] In a DTH (delayed-type hypersensitivity) mouse model, Dalazatide (2 mg/kg i.v.) suppressed TEM cell-mediated inflammation by inhibiting T-cell migration to inflamed tissues and reducing cytokine production. Intravital imaging confirmed reduced TEM cell motility at challenge sites [3] For SLE, preclinical studies demonstrated that Dalazatide ameliorated autoantibody production and renal pathology in lupus-prone mice by selectively targeting autoreactive TEM cells [2] |
| Cell Assay |
cell proliferation assay [3] Cell Types: CCR7− T cells [3] Tested Concentrations: 0- 100nM Incubation Duration: 3 days Experimental Results: Inhibits cell proliferation, IC50 is 180±37pM. TEM cells were isolated from human PBMCs or SLE patient blood. Kv1.3 currents were recorded via patch-clamp electrophysiology. Calcium flux was measured using Fluo-4 AM dye after TCR stimulation with anti-CD3/anti-CD28 antibodies [2] Cytokine secretion (IFN-γ, TNF-α, IL-17) was quantified by ELISA following 48-hour TEM cell activation. Proliferation was assessed via [³H]-thymidine incorporation [2] For DTH imaging, murine TEM cells were labeled with CFSE and adoptively transferred. Two-photon intravital microscopy tracked cell motility in ear pinnae after antigen challenge [3] |
| Animal Protocol |
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] |
| ADME/Pharmacokinetics |
Phase 1b data (psoriasis) showed subcutaneous Dalazatide had a half-life of ~1.3 hours and dose-proportional exposure (Cmax and AUC). Bioavailability was >80% [1] |
| Toxicity/Toxicokinetics |
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] |
| References |
[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. |
| Additional Infomation |
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] |
Solubility Data
| Solubility (In Vitro) | 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 |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.2251 mL | 1.1256 mL | 2.2512 mL | |
| 5 mM | 0.0450 mL | 0.2251 mL | 0.4502 mL | |
| 10 mM | 0.0225 mL | 0.1126 mL | 0.2251 mL |