Chlorotoxin

Last updated
Chlorotoxin
Chlorotoxin.png
Names
IUPAC name
L-methionyl-L-cysteinyl-L-methionyl-L-prolyl-L-cysteinyl-L-phenylalanyl-L-threonyl-L-threonyl-L-.alpha.-aspartyl-L-histidyl-L-glutaminyl-L-methionyl-L-alanyl-L-arginyl-L-lysyl-L-cysteinyl-L-α-aspartyl-L-α-aspartyl-L-cysteinyl-L-cysteinylglycylglycyl-L-lysylglycyl-L-arginylglycyl-L-lysyl-L-cysteinyl-L-tyrosylglycyl-L-prolyl-L-glutaminyl-L-cysteinyl-L-leucyl-L-cysteinyl-L-argininamide, cyclic (219),(528),(1633),(2035)-tetrakis(disulfide)
Other names
MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C158H249N53O47S11/c1-77(2)55-96-138(241)205-105(144(247)186-86(125(165)228)28-18-47-173-156(166)167)70-264-262-68-103-131(234)177-63-115(217)176-64-116(218)183-87(25-12-15-44-159)128(231)178-65-117(219)184-88(29-19-48-174-157(168)169)129(232)179-66-118(220)185-89(26-13-16-45-160)133(236)202-107-72-267-269-75-110-149(252)195-98(56-81-23-10-9-11-24-81)143(246)208-124(80(5)213)154(257)209-123(79(4)212)153(256)199-102(61-122(226)227)141(244)196-99(58-83-62-172-76-181-83)139(242)189-92(37-39-113(163)215)136(239)190-94(42-53-260-7)132(235)182-78(3)126(229)187-91(30-20-49-175-158(170)171)134(237)188-90(27-14-17-46-161)135(238)203-108(73-266-265-71-106(146(249)193-96)204-137(240)93(38-40-114(164)216)191-151(254)111-31-21-50-210(111)119(221)67-180-130(233)97(194-147(107)250)57-82-33-35-84(214)36-34-82)148(251)198-100(59-120(222)223)140(243)197-101(60-121(224)225)142(245)206-109(150(253)201-103)74-268-263-69-104(200-127(230)85(162)41-52-259-6)145(248)192-95(43-54-261-8)155(258)211-51-22-32-112(211)152(255)207-110/h9-11,23-24,33-36,62,76-80,85-112,123-124,212-214H,12-22,25-32,37-61,63-75,159-162H2,1-8H3,(H2,163,215)(H2,164,216)(H2,165,228)(H,172,181)(H,176,217)(H,177,234)(H,178,231)(H,179,232)(H,180,233)(H,182,235)(H,183,218)(H,184,219)(H,185,220)(H,186,247)(H,187,229)(H,188,237)(H,189,242)(H,190,239)(H,191,254)(H,192,248)(H,193,249)(H,194,250)(H,195,252)(H,196,244)(H,197,243)(H,198,251)(H,199,256)(H,200,230)(H,201,253)(H,202,236)(H,203,238)(H,204,240)(H,205,241)(H,206,245)(H,207,255)(H,208,246)(H,209,257)(H,222,223)(H,224,225)(H,226,227)(H4,166,167,173)(H4,168,169,174)(H4,170,171,175)/t78-,79+,80+,85-,86-,87-,88-,89-,90-,91-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,123-,124-/m0/s1
    Key: QPAKKWCQMHUHNI-GQIQPHNSSA-N
  • C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@H]4C(=O)NCC(=O)NCC(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)CCSC)CCC(=O)N)CC5=CNC=N5)CC(=O)O)[C@@H](C)O)[C@@H](C)O)CC6=CC=CC=C6)NC(=O)[C@@H]7CCCN7C(=O)[C@@H](NC(=O)[C@H](CSSC[C@@H](C(=O)N4)NC(=O)[C@@H](NC(=O)[C@@H](NC2=O)CC(=O)O)CC(=O)O)NC(=O)[C@H](CCSC)N)CCSC)C(=O)N[C@H](C(=O)NCC(=O)N8CCC[C@H]8C(=O)N[C@H](C(=O)N3)CCC(=O)N)CC9=CC=C(C=C9)O)CCCCN)CCCNC(=N)N)CCCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N)CC(C)C)CCCCN)CCCNC(=N)N
Properties
C158H249N53O47S11
Molar mass 3995.71 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Chlorotoxin is a 36-amino acid peptide found in the venom of the deathstalker scorpion (Leiurus quinquestriatus) which blocks small-conductance chloride channels. [2] The fact that chlorotoxin binds preferentially to glioma cells has allowed the development of methods for the treatment and diagnosis of several types of cancer. [3]

Contents

Sources

Chlorotoxin can be purified from crude leiurus, which belongs to the scorpion toxin protein superfamily. [4]

Chemistry

Chlorotoxin is a small toxin and at pH 7 is highly positively charged. It is a peptide consisting of 36 amino acids, with 8 cysteines forming 4 disulfide bonds. [5] Chlorotoxin has a considerable sequence homology to the class of small insectotoxins. [4] [6]

Target

Chlorotoxin is the first reported high-affinity peptide ligand for Cl− channels and it blocks small conductance chloride channels. Each chloride channel can be closed by only one ligand molecule. [2] [4]

Using a recombinant chlorotoxin it was demonstrated that chlorotoxin specifically and selectively interacts with MMP-2 isoforms which are specifically upregulated in gliomas and related cancers, but are not normally expressed in brain. [3]

Toxicity

Chlorotoxin immobilizes the envenomated prey. Duration of paralysis depends on the amount of chlorotoxin injected. In crayfish, chlorotoxin at 1.23-2.23 µg/g body wt produced a loss of motor control beginning about 20 seconds after injection which progressed to a rigid paralysis of the walking and pincer legs that was complete about forty seconds later. Within ±90 s of injection the tail musculature was immobilized. No recovery was noted for 6 hours, at which time the crayfish were destroyed. At 0.5 µg/g, chlorotoxin induced the same progressive paralysis with a slower onset. Recovery of crayfish was noted after 2 hours. The injection on insects produced similar results to those observed in crayfish. [4]

Possible therapeutic use

The fact that chlorotoxin binds preferentially to glioma cells compared with non-neoplastic cells or normal brain has allowed the development of new methods for the treatment and diagnosis of several types of cancer. [7]

Chlorotoxin has the ability to interact with chloride channels in membrane protein in glioma cells, so this prevents transmembrane chloride fluxes but this interaction does not happen for the neurons and normal glial cells. This suggests a potential treatment for cancer. [8]

A report showed the anti-invasive effect of chlorotoxin on glioma cells mediated by its interaction with MMP-2, which allows the penetration of normal and tumor cells through tissue barriers. Chlorotoxin exerts a dual effect on MMP-2: it inhibits the enzymatic activity of MMP-2 and causes a reduction in the surface expression of MMP-2. This result implies the use of chlorotoxin as a highly effective drug of therapeutic potential for diseases that involve the activity of MMP-2. [3]

TM-601 which is the synthetic version of chlorotoxin is under phase II clinical trial. Iodine-131-TM-601 is used to treat malignant glioma. TM-601 is also a candidate for targeting gliomas because it crosses blood-brain and tissue barriers and binds to malignant brain tumor cells without affecting healthy tissue. [9]

Phase II trials are being conducted on the use of chlorotoxin for imaging and radio therapy in glioma. [10]

Chlorotoxin:Cy5.5 (CTX:Cy5.5), which is a bioconjugate of chlorotoxin and a fluorescent dye named Cy5.5, was used by researchers at Seattle Children's Hospital Research Institute and Fred Hutchinson Cancer Research Center to distinguish cancer cells from the surrounding normal cells. [11] This could enable surgeons to remove cancerous cells without injuring the surrounding healthy tissue. CTX:Cy5.5 is a fluorescent molecule emitting photons in the near infrared spectrum and hence can be visualized in the operating room with the aid of infrared glasses. Studies in mouse models have shown that CTX:Cy5.5 can identify tumors with as few as 2000 cancer cells, making it 500 times more sensitive than MRI. Treated animals exhibited no neurologic or behavioral deficits, and postmortem studies revealed no evidence of neuropathy. [12] In 2015, clinical trials were beginning for this "Tumor Paint." [13]

In the episode "Both Sides Now" of medical drama House , House suggests using a scorpion derived toxin to paint the pancreas and view it under infrared light to look for tumors too small to detect by MRI. [14]

Related Research Articles

<span class="mw-page-title-main">Charybdotoxin</span> Chemical compound, scorpion neurotoxin

Charybdotoxin (ChTX) is a 37 amino acid neurotoxin from the venom of the scorpion Leiurus quinquestriatus hebraeus (deathstalker) that blocks calcium-activated potassium channels. This blockade causes hyperexcitability of the nervous system. It is a close homologue of agitoxin and both toxins come from Leiurus quinquestriatus hebraeus. It is named after Charybdis, a sea monster from Greek myth.

<span class="mw-page-title-main">Deathstalker</span> Species of arachnid

The deathstalker is a species of scorpion, a member of the family Buthidae. It is also known as the Palestine yellow scorpion, Omdurman scorpion, and Naqab desert scorpion, as well as by many other colloquial names, which generally originate from the commercial captive trade of the animal. To eliminate confusion, especially important with potentially dangerous species, the scientific name is normally used to refer to them. The name Leiurus quinquestriatus roughly translates into English as "five-striped smooth-tail". In 2014, the subspecies L. q. hebraeus was separated from it and elevated to its own species Leiurus hebraeus. Other species of the genus Leiurus are also often referred to as "deathstalkers". Leiurus quinquestriatus is yellow, and 30–77 millimetres (1.2–3.0 in) long, with an average of 58 mm (2.3 in).

Tityustoxin is a toxin found in the venom of scorpions from the subfamily Tityinae. By binding to voltage-dependent sodium ion channels and potassium channels, they cause sialorrhea, lacrimation and rhinorrhea.

<span class="mw-page-title-main">Scyllatoxin</span> Scorpion toxin

Scyllatoxin (also leiurotoxin I) is a toxin, from the scorpion Leiurus quinquestriatus hebraeus, which blocks small-conductance Ca2+-activated K+ channels. It is named after Scylla, a sea monster from Greek mythology. Charybdotoxin is also found in the venom from the same species of scorpion, and is named after the sea monster Charybdis. In Greek mythology, Scylla and Charybdis lived on rocks on opposing sides of a narrow strait of water.

<span class="mw-page-title-main">Agitoxin</span>

Agitoxin is a toxin found in the venom of the scorpion Leiurus quinquestriatus hebraeus. Other toxins found in this species include charybdotoxin (CTX). CTX is a close homologue of Agitoxin.

<span class="mw-page-title-main">Scorpion toxin</span>

Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, voltage-gated sodium channels, voltage-gated potassium channels, and Transient Receptor Potential (TRP) channels. The result of this action is to activate or inhibit the action of these channels in the nervous and cardiac organ systems. For instance, α-scorpion toxins MeuNaTxα-12 and MeuNaTxα-13 from Mesobuthus eupeus are neurotoxins that target voltage-gated Na+ channels (Navs), inhibiting fast inactivation. In vivo assays of MeuNaTxα-12 and MeuNaTxα-13 effects on mammalian and insect Navs show differential potency. These recombinants exhibit their preferential affinity for mammalian and insect Na+ channels at the α-like toxins' active site, site 3, in order to inactivate the cell membrane depolarization faster[6]. The varying sensitivity of different Navs to MeuNaTxα-12 and MeuNaTxα-13 may be dependent on the substitution of a conserved Valine residue for a Phenylalanine residue at position 1630 of the LD4:S3-S4 subunit or due to various changes in residues in the LD4:S5-S6 subunit of the Navs. Ultimately, these actions can serve the purpose of warding off predators by causing pain or to subdue predators.

Imperatoxin I (IpTx) is a peptide toxin derived from the venom of the African scorpion Pandinus imperator.

<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

BmTx3 is a neurotoxin, which is a component of the venom of the scorpion Buthus Martensi Karsch. It blocks A-type potassium channels in the central nervous system and hERG-channels in the heart.

<span class="mw-page-title-main">Lq2</span>

Lq2 is a component of the venom of the scorpion Leiurus quinquestriatus. It blocks various potassium channels, among others the inward-rectifier potassium ion channel ROMK1.

<span class="mw-page-title-main">Psalmotoxin</span>

Psalmotoxin (PcTx1) is a spider toxin from the venom of the Trinidad tarantula Psalmopoeus cambridgei. It selectively blocks Acid Sensing Ion Channel 1-a (ASIC1a), which is a proton-gated sodium channel.

Ergtoxin is a toxin from the venom of the Mexican scorpion Centruroides noxius. This toxin targets hERG potassium channels.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

<span class="mw-page-title-main">ImKTx88</span>

ImKTx88 is a selective inhibitor of the Kv1 ion channel family that can be isolated from the venom of the Isometrus maculatus. This peptide belongs to the α-KTx subfamily and is classified as a pore-blocking toxin.

LqhIT2 is a long-chain scorpion depressant β-toxin derived from Leiurus quinquestriatus hebraeus. It targets insect voltage-gated sodium channels (Navs) and shifts the voltage dependence of channel activation to a more negative membrane potential.

<i>Leiurus hebraeus</i> Species of scorpion

Leiurus hebraeus, the Hebrew deathstalker, is a species of scorpion, a member of the family Buthidae. It is also known as the Israeli yellow scorpion, It was once considered as a subspecies of Leiurus quinquestriatus but recently it was elevated to the rank of a species. It is currently known from Israel, but it may live in other countries in the Middle East. Other species of the genus Leiurus are also often referred to as "deathstalkers".

<i>Leiurus abdullahbayrami</i> Species of scorpion

Leiurus abdullahbayrami is a species of scorpion in the family Buthidae. Its venom is highly toxic to humans, but can be used in medical development.

Humans use scorpions both practically, for medicine, food, and pets, and symbolically, whether as gods, to ward off harm, or to associate a product or business with the evident power of the small but deadly animal.


N58A is a peptide depressant β-neurotoxin found in the venom of certain East Asian scorpions. The toxin affects voltage-gated sodium channels, specifically Nav1.8 & Nav1.9 channels.

The CmERG1 toxin is a peptide composed of 42 amino acids, found in venom from the Colombian scorpion Centruroides margaritatus. It blocks human ether-a-go-go-Related gene (hERG) potassium channels, which are important for cardiac action potential repolarization.

References

  1. ↑ "Chlorotoxin from Leiurus quinquestriatus (north Africa)". Sigmaaldrich.com. Retrieved November 30, 2021.
  2. 1 2 DeBin JA, Strichartz GR (1991). "Chloride channel inhibition by the venom of the scorpion Leiurus quinquestriatus". Toxicon. 29 (11): 1403–8. doi:10.1016/0041-0101(91)90128-E. PMID   1726031.
  3. 1 2 3 Deshane J, Garner CC, Sontheimer H (February 2003). "Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2". J. Biol. Chem. 278 (6): 4135–44. doi: 10.1074/jbc.M205662200 . PMID   12454020.
  4. 1 2 3 4 DeBin JA, Maggio JE, Strichartz GR (February 1993). "Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion". Am. J. Physiol. 264 (2 Pt 1): C361–9. doi:10.1152/ajpcell.1993.264.2.C361. PMID   8383429.
  5. ↑ Lippens G, Najib J, Wodak SJ, Tartar A (January 1995). "NMR sequential assignments and solution structure of chlorotoxin, a small scorpion toxin that blocks chloride channels". Biochemistry. 34 (1): 13–21. doi:10.1021/bi00001a003. PMID   7819188.
  6. ↑ Wudayagiri R, Inceoglu B, Herrmann R, Derbel M, Choudary PV, Hammock BD (2001). "Isolation and characterization of a novel lepidopteran-selective toxin from the venom of South Indian red scorpion, Mesobuthus tamulus". BMC Biochem. 2: 16. doi: 10.1186/1471-2091-2-16 . PMC   64496 . PMID   11782289.
  7. ↑ Soroceanu L, Gillespie Y, Khazaeli MB, Sontheimer H (November 1998). "Use of chlorotoxin for targeting of primary brain tumors". Cancer Res. 58 (21): 4871–9. PMID   9809993.
  8. ↑ Lyons SA, O'Neal J, Sontheimer H (August 2002). "Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin". Glia. 39 (2): 162–73. doi:10.1002/glia.10083. PMID   12112367. S2CID   8513870.
  9. ↑ Mamelak AN, Rosenfeld S, Bucholz R, et al. (August 2006). "Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma". J. Clin. Oncol. 24 (22): 3644–50. doi:10.1200/JCO.2005.05.4569. PMID   16877732.
  10. ↑ Mark R. Stroud; Stacey J. Hansen; James M. Olson (December 2011). "In Vivo Bio Imaging Using Chlorotoxin Based Conjugates". Current Pharmaceutical Design. 17 (38): 4362–71. doi:10.2174/138161211798999375. PMC   3272502 . PMID   22204434.
  11. ↑ Veiseh M, Gabikian P, Bahrami SB, et al. (July 2007). "Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci". Cancer Res. 67 (14): 6882–8. doi: 10.1158/0008-5472.CAN-06-3948 . PMID   17638899.
  12. ↑ "Tumor Painting Revolutionizes Fight Against Cancer". 15 July 2007. Archived from the original on 4 June 2016. Retrieved 11 September 2015.
  13. ↑ Fidel, J.; Kennedy, K. C.; Dernell, W. S.; Hansen, S.; Wiss, V.; Stroud, M. R.; Molho, J. I.; Knoblaugh, S. E.; Meganck, J.; Olson, J. M.; Rice, B.; Parrish-Novak, J. (2015). "Preclinical validation of the utility of BLZ-100 in providing fluorescence contrast for imaging canine spontaneous solid tumors". Cancer Research. 75 (20): 4283–4291. doi:10.1158/0008-5472.CAN-15-0471. PMC   4610180 . PMID   26471914.
  14. ↑ "Both Sides Now synopsis". IMDb.com. Retrieved 30 November 2015.
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