ShK-Dap22

Extremely potent and selective KV1.3 blocker; suppresses T cell activation in vitro CAS# 220384-25-8

ShK-Dap22

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Chemical structure

ShK-Dap22

3D structure

Chemical Properties of ShK-Dap22

Cas No. 220384-25-8 SDF Download SDF
PubChem ID 90488816 Appearance Powder
Formula C166H268N54O48S7 M.Wt 4012.7
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 1 mg/ml in water
Sequence RSCIDTIPKSRCTAFQCKHSMXYRLSFCRKTCGTC

(Modifications: Disulfide bridges: 3-35,12-28,17-32), X= Dap)

SMILES CCC(C)C1C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N2CCCC2C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC3CSSCC4C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N4)CC5=CC=CC=C5)CO)CC(C)C)CCCNC(=N)N)CC6=CC=C(C=C6)O)CN)CCSC)CO)CC7=CNC=N7)CCCCN)NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC3=O)C(C)O)C)CC8=CC=CC=C8)CCC(=O)N)C(=O)NCC(=O)NC(C(=O)NC(CSSCC(C(=O)N1)NC(=O)C(CO)NC(=O)C(CCCNC(=N)N)N)C(=O)O)C(C)O)C(C)O)CCCCN)CCCNC(=N)N)CCCNC(=N)N)CO)CCCCN)C(C)CC)C(C)O)CC(=O)O
Standard InChIKey PFWOJTLVNOZSGQ-UHFFFAOYSA-N
Standard InChI InChI=1S/C166H268N54O48S7/c1-13-81(5)123-156(261)202-107(65-122(232)233)145(250)218-128(87(11)228)160(265)216-124(82(6)14-2)161(266)220-58-31-43-119(220)155(260)196-95(38-22-25-52-168)135(240)205-110(70-222)147(252)191-99(42-30-57-185-166(179)180)136(241)209-117-77-273-272-75-115-152(257)193-97(40-28-55-183-164(175)176)132(237)189-96(39-23-26-53-169)139(244)217-127(86(10)227)159(264)212-113(131(236)186-68-121(231)214-125(84(8)225)158(263)213-118(162(267)268)78-275-274-76-116(153(258)215-123)211-150(255)109(69-221)204-130(235)93(171)36-27-54-182-163(173)174)73-270-271-74-114(208-137(242)100(48-49-120(172)230)194-141(246)103(61-88-32-17-15-18-33-88)197-129(234)83(7)188-157(262)126(85(9)226)219-154(117)259)151(256)192-94(37-21-24-51-167)133(238)201-106(64-91-67-181-79-187-91)144(249)207-111(71-223)148(253)195-101(50-59-269-12)138(243)203-108(66-170)146(251)199-105(63-90-44-46-92(229)47-45-90)142(247)190-98(41-29-56-184-165(177)178)134(239)198-102(60-80(3)4)140(245)206-112(72-224)149(254)200-104(143(248)210-115)62-89-34-19-16-20-35-89/h15-20,32-35,44-47,67,79-87,93-119,123-128,221-229H,13-14,21-31,36-43,48-66,68-78,167-171H2,1-12H3,(H2,172,230)(H,181,187)(H,186,236)(H,188,262)(H,189,237)(H,190,247)(H,191,252)(H,192,256)(H,193,257)(H,194,246)(H,195,253)(H,196,260)(H,197,234)(H,198,239)(H,199,251)(H,200,254)(H,201,238)(H,202,261)(H,203,243)(H,204,235)(H,205,240)(H,206,245)(H,207,249)(H,208,242)(H,209,241)(H,210,248)(H,211,255)(H,212,264)(H,213,263)(H,214,231)(H,215,258)(H,216,265)(H,217,244)(H,218,250)(H,219,259)(H,232,233)(H,267,268)(H4,173,174,182)(H4,175,176,183)(H4,177,178,184)(H4,179,180,185)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of ShK-Dap22

DescriptionExtremely potent KV1.3 channel blocker (Kd = 23 pM for mKV1.3 currents). Selective for KV1.3 over other mammalian potassium channels (IC50 values are 23, 1800, 10500, 37000 and 39000 pM for mKV1.3, mKV1.1, hKV1.6, mKV1.4 and rKV1.2 respectively, and >100000 pM for hKV1.5, mKV1.7, hKV3.1, rKV3.4 and hKCa4). Suppresses T cell activation in vitro (IC50 < 500 pM).

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References on ShK-Dap22

ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide.[Pubmed:9830012]

J Biol Chem. 1998 Dec 4;273(49):32697-707.

The voltage-gated potassium channel in T lymphocytes, Kv1.3, is an important molecular target for immunosuppressive agents. A structurally defined polypeptide, ShK, from the sea anemone Stichodactyla helianthus inhibited Kv1.3 potently and also blocked Kv1.1, Kv1.4, and Kv1.6 at subnanomolar concentrations. Using mutant cycle analysis in conjunction with complementary mutagenesis of ShK and Kv1.3, and utilizing the structure of ShK, we determined a likely docking configuration for this peptide in the channel. Based upon this topological information, we replaced the critical Lys22 in ShK with the positively charged, non-natural amino acid diaminopropionic acid (ShK-Dap22) and generated a highly selective and potent blocker of the T-lymphocyte channel. ShK-Dap22, at subnanomolar concentrations, suppressed anti-CD3 induced human T-lymphocyte [3H]thymidine incorporation in vitro. Toxicity with this mutant peptide was low in a rodent model, with a median paralytic dose of approximately 200 mg/kg body weight following intravenous administration. The overall structure of ShK-Dap22 in solution, as determined from NMR data, is similar to that of native ShK toxin, but there are some differences in the residues involved in potassium channel binding. Based on these results, we propose that ShK-Dap22 or a structural analogue may have use as an immunosuppressant for the prevention of graft rejection and for the treatment of autoimmune diseases.

Substitution of a single residue in Stichodactyla helianthus peptide, ShK-Dap22, reveals a novel pharmacological profile.[Pubmed:14622016]

Biochemistry. 2003 Nov 25;42(46):13698-707.

ShK, a peptide isolated from Stichodactyla helianthus venom, blocks the voltage-gated potassium channels, K(v)1.1 and K(v)1.3, with similar high affinity. ShK-Dap(22), a synthetic derivative in which a diaminopropionic acid residue has been substituted at position Lys(22), has been reported to be a selective K(v)1.3 inhibitor and to block this channel with equivalent potency as ShK [Kalman et al. (1998) J. Biol. Chem. 273, 32697-32707]. In this study, a large body of evidence is presented which indicates that the potencies of wild-type ShK peptide for both K(v)1.3 and K(v)1.1 channels have been previously underestimated. Therefore, the affinity of ShK-Dap(22) for both channels appears to be ca. 10(2)-10(4)-fold weaker than ShK. ShK-Dap(22) does display ca. 20-fold selectivity for human K(v)1.3 vs K(v)1.1 when measured by the whole-cell voltage clamp method but not in equilibrium binding assays. ShK-Dap(22) has low affinity for K(v)1.2 channels, but heteromultimeric K(v)1.1-K(v)1.2 channels form a receptor with ca. 200-fold higher affinity for ShK-Dap(22) than K(v)1.1 homomultimers. In fact, K(v)1.1-K(v)1.2 channels bind ShK-Dap(22) with only ca. 10-fold less potency than ShK and reveal a novel pharmacology not predicted from the homomultimers of K(v)1.1 or K(v)1.2. The concentrations of ShK-Dap(22) needed to inhibit human T cell activation were ca. 10(3)-fold higher than those of ShK, in good correlation with the relative affinities of these peptides for inhibiting K(v)1.3 channels. All of these data, taken together, suggest that ShK-Dap(22) will not have the same in vivo immunosuppressant efficacy of other K(v)1.3 blockers, such as margatoxin or ShK. Moreover, ShK-Dap(22) may have undesired side effects due to its interaction with heteromultimeric K(v)1.1-K(v)1.2 channels, such as those present in brain and/or peripheral tissues.

Hypoxia modulates early events in T cell receptor-mediated activation in human T lymphocytes via Kv1.3 channels.[Pubmed:15677684]

J Physiol. 2005 Apr 1;564(Pt 1):131-43.

T lymphocytes are exposed to hypoxia during their development and when they migrate to hypoxic pathological sites. Although it has been shown that hypoxia inhibits Kv1.3 channels and proliferation in human T cells, the mechanisms by which hypoxia regulates T cell activation are not fully understood. Herein we test the hypothesis that hypoxic inhibition of Kv1.3 channels induces membrane depolarization, thus modulating the increase in cytoplasmic Ca2+ that occurs during activation. Hypoxia causes membrane depolarization in human CD3+ T cells, as measured by fluorescence-activated cell sorting (FACS) with the voltage-sensitive dye DiBAC4(3). Similar depolarization is produced by the selective Kv1.3 channel blockers ShK-Dap22 and margatoxin. Furthermore, pre-exposure to such blockers prevents any further depolarization by hypoxia. Since membrane depolarization is unfavourable to the influx of Ca2+ through the CRAC channels (necessary to drive many events in T cell activation such as cytokine production and proliferation), the effect of hypoxia on T cell receptor-mediated increase in cytoplasmic Ca2+ was determined using fura-2. Hypoxia depresses the increase in Ca2+ induced by anti-CD3/CD28 antibodies in approximately 50% of lymphocytes. In the remaining cells, hypoxia either did not elicit any change or produced a small increase in cytoplasmic Ca2+. Similar effects were observed in resting and pre-activated CD3+ cells and were mimicked by ShK-Dap22. These effects appear to be mediated solely by Kv1.3 channels, as we find no influence of hypoxia on IKCa1 and CRAC channels. Our findings indicate that hypoxia modulates Ca2+ homeostasis in T cells via Kv1.3 channel inhibition and membrane depolarization.

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