Venom Peptides and their Mimetics
as Potential Drugs
Oren Bogin, Ph.D.
Venomous creatures have a sophisticated mechanism for prey capture which includes a vast array of biologically-active compounds, such as enzymes, proteins, peptides and small molecular weight compounds. These substances target an immense number of receptors and membrane proteins with high affinity, selectivity and potency, and can serve as potential drugs or scaffolds for drug design. channels has been established13 (please refer to the article "Contribution of Ion Channels in A large number of organisms produce and secrete Recurrent pain was recently termed the "silent Pain Sensation" in this Modulator issue). Pain venoms to defend themselves and to capture epidemic", since one out of six people in the signals can be blocked at a number of sites along prey. Venom is a rich source of biochemically western world suffers from pain, costing the the pain pathway (See Figure). The large list of active enzymes, proteins, peptides and low American public alone approximately $100 neurotransmitters and receptors identified along molecular weight substances. Toxins isolated billion each year in health care, compensation, the pain pathway indicate that there may be many from the venom either inhibit or activate a and litigation.
therapeutic possibilities for the pharmacological 11,12 Chronic pain is associated vast number of targets such as ion channels, with conditions such as back injury, migraine control of the transmission of nociceptive acetylcholine receptors, acetylcholinesterase, headaches, arthritis, herpes zoster, diabetic information to the brain. membranes, coagulant/anticoagulant pathways, neuropathy, temporomandibular joint syndrome, and metalloproteases, with high selectivity and cancer. Effective treatment options are Voltage-Gated Ca2+ Channels (VGCC) and affinity. They can be roughly divided into limited to opioids (morphine and related drugs) Ca 2.2 (α1B, N-type) was shown to control non-peptide and peptide toxins. Non-peptide and non-steroidal anti-inflammatories (NSAIDs), transmission at CNS and PNS synapses including toxins have been isolated from algae, plants, yet opioids have significant potential side effects, in the transmission of pain signals at the spinal dinoflagellate, fish and from higher organisms and NSAIDs are ineffective for moderate-to-severe level. A PNS-specific Ca 2.2 splice variant is highly which accumulate alkaloids through their diet pain. Pain can be generated by nociceptors expressed in the superficial layer of the dorsal as exemplified in toxic frogs. Peptide toxins are stimulated by thermal, mechanical, chemical or horn, which is considered to be responsible for generally synthesized in the venomous ducts of inflammatory response, and a pivotal role for ion the nociceptive pathway of the spinal cord.14 poisonous creatures. The majority of the data Ca 2.2 was found to be up-regulated in the spinal acquired to date has been from toxins isolated cord during chronic pain states, along with the from the venoms of snakes, scorpions, spiders, Pain pathways and pain signaling auxiliary α2δ-1 subunit.15,16 Blockers of N-type marine snails (Conus genus) and sea anemones. channels were shown to block Ca2+ influx and thus Toxins isolated from venomous animals are the release of substance P in the spinal cord.17 usually small, ranging from 8-70 amino acids, Furthermore, N-type channels are susceptible to with relatively small scaffold structures, which are modulation by µ-opioid peptide receptor agonists, highly compact and stabilized by either disulfide such as morphine.18 Recently it was proposed bonds or by hydrogen bonds made from post- that T-type and possibly P/Q-Type Ca2+ channels transational-modified amino acids. In a number may participate in pain pathways, and may serve of toxins, the active residues responsible for the as possible therapeutic targets.14,19,20 toxin activity have been identified, thus enabling the rational design of small molecular weight compounds or peptomimetics. 1- Voltage-Gated Na+ Channels 2- Voltage-Gated Ca2+ Channels The pharmaceutical industry has recognized 3- Neuronal Nicotinic Acetylcholine the enormous potential inherent in these venom peptides and has begun to exploit the selectivity and sensitivity fine tuned by evolution. This Neurotensin Receptor Agonist review will focus on peptides and toxin mimetics NMDA Receptor Antagonist that are currently being evaluated as possible drugs for the treatment of pain, epilepsy, Pain can be generated by nociceptors from a number of cardiovascular disorders, cancer and other stimuli including, heat, cold, mechanosensation, inflammation, neurological disorders (See Table), (for recent and injury and pH. Venom toxins intersect pain signaling by inhibiting comprehensive reviews please refer to references or stimulating channels and receptors along the pathway. The possible localization of the pain pathway targets are illustrated above.
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A large array of VGCC peptide inhibitors were structure of ω-Conotoxin CVID against virtual which are activated by the alkaloid, nicotine. isolated from the venoms of cone snails, spiders screening libraries resulting in a cyclic peptide These pentameric conductance channels for and snakes. The most selective inhibitors of N- with D-amino acids having an IC of 20 µM and Ca2+, K+, and Na+ are formed from a number of type Ca2+ channels known to date were isolated apparent selectivity between N- and P/Q- type homologous subunits, and various combinations from Conus geographus (ω-Conotoxin GVIA), VGCC.27 Furthermore, using alkylphenyl ether of these subunits result in channels which differ Conus magus (ω-Conotoxin MVIIA), and Conus based analogues which mimic three key amino in their pharmacology and tissue distribution.34 catus, (ω-Conotoxin CVID). ω-Conotoxin MVIIA, acids of the toxins (Arg-10, Leu-11 and Tyr-13), A class of conotoxins block nAChR and can a 25 amino acid peptide is a highly potent and leads to three compounds which have an apparent differentiate between neuronal, skeletal muscle selective blocker of N-type VGCC.21 A synthetic IC of 3 µM.28 These and other experiments and sub-population isoforms of receptors, ω-Conotoxin MVIIA analog, PrialtTM (previously show that it is possible to design smaller entities termed α- and αΑ- Conotoxins.3,8,35 The latter called SNX-111 and Ziconotide) initially developed which are active and selective.
toxins are termed alpha toxins as compared to by Neurex Corporation and currently being a similarly acting α-Bungarotoxin, a blocker of commercialized by Elan Corporation for the Voltage-Gated Na+ Channels (VGSC) muscle-type nAChR . Attempts to understand treatment of severe chronic infl ammatory and VGSC modulators have been isolated from the mechanism of the selectivity have been neuropathic pain associated with cancer and the venom of a variety of organisms, including reported.36,37 The α-Conotoxins inhibit the AIDS.22,23 Although injected intrathecally, it was spiders, sea anemones, scorpions, and cone signal transmission at the postsynaptic junction shown that PrialtTM is about 1000-fold more snails.1,8 There is a great need for specifi c venom (neuronal or neuromuscular), by binding to the potent then morphine, lacking the tolerance peptides that can discriminate between the α-subunits of the nAChR, thus blocking the or addiction usually associated with opiates.24 different VGSCs. A possibly abundant source binding of acetylcholine and other agonists, However,PrialtTM administration results in severe for VGSC modulators was found in the venoms which in turn inhibits the infl ux of Na+ required side effects, including hypotension, sedation of cone snail venoms. Two main classes of for action potential propagation. and confusion.25 During December 2004, conotoxins that affect VGSC are the µ- and δ- Elan Corporation was granted FDA approval Conotoxins.3,8 Recently the µ-Conotoxin SmIIIA α-Conopeptide Vc1.1 (other name ACV1), is a forPrialtTM (ziconotide intrathecal infusion) for the toxin was isolated from the venom of Conus 16 amino acid peptide, containing two disulfi de management of severe chronic pain. ω-Conotoxin stercusmuscarum, which has been shown to block bonds. Its sequence was deduced from the CVID analog, AM336, which is being developed TTX-R currents in amphibian sympathetic and nucleotide sequence of the conopeptide gene by Amrad Corporation, has been in Phase II sensory neurons.32,33 The authors speculate that cDNA amplifi ed from mRNA extracted from clinical trial since 2002 with cancer patients the irreversible current block in the frog DRG was the venom duct of Conus victoriae. Vc1.1 was suffering severe chronic pain. AM336 was shown by inhibition of Na 1.8 and Na 1.9 channels, while active as an antagonist of neuronal nAChRs to inhibit a PNS-specifi c splice variant N-type the reversible inhibition of frog skeletal muscle is in receptor binding and functional studies on VGCC associated with transmitter release from due to Na 1.4 channel inhibition.32 bovine chromaffi n cells. It also suppressed the preganglionic nerve terminal and displays a wider µ-Conotoxin SmIIIA or its mimetics may be an vascular responses to C-fi ber activation, and therapeutic index than ω-Conotoxin MVIIA.17,26 attractive toxin for pain treatment. accelerated the functional recovery of injured Recently, attempts were made to "convert" the peripheral nerves in rats. These peripheral toxin's pivotal binding residues into smaller Neuronal Nicotinic Acetylcholine Receptors unmyelinated sensory nerves are involved molecular weight compounds, which might have in pain transmission.38 Recently, Metabolic superior pharmacological qualities in terms of Nicotinic acetylcholine receptors (nAChRs) are Pharmaceuticals Ltd., who are developing formulation, production, metabolic stability a family of ligand-gated cation channels whose ACV1 as an analgesic for the treatment and delivery.27-31 One approach compared the endogenous ligand is acetylcholine (ACh) and of chronic neuropathic pain, has begun rTamapinA Novel Blocker of K 2 (SK; small conductance Ca2+-activated K+) Channels Tamapin (#RTT-400) is a 31 amino acid peptidyl toxin, isolated from the venom of the Indian red scorpion, Mesobuthus tamulus, and is classified as α-5.4 scorpion toxin family (P59869).1,2 Native Tamapin blocks K 2 channels in pyramidal neurons of the hippocampus as well as in cell lines expressing distinct K 2 channel subunits. Tamapin displays a remarkable selectivity for K 2.2 (SK2/KCNN2, IC =24pM) versus K 2.1 (SK1/KCNN1, 1750-fold) and K 2.3 (SK3/KCNN3, 70-fold) channels.3 500nM of rTamapin completely blocked K 2.2 mediated currents in Xenopus oocytes.
1. Doorty, K.B. et al. (2001) Toxicon. 39, 137.
2. Rodriguez de la Vega, R.C. and Possani, L.D. (2004), Toxicon, 43, 865.
3. Pedarzani, P. et al. (2002) J. Biol. Chem. 277, 46101.
Activation of rTamapin (#RTT-400) sensitive outward current by Model structure of Tamapin, based on its homology to intracellular Ca2+ injection into Xenopus oocytes expressing SK2 scyllatoxin (1SCY). This class of peptides possesses the (K 2.2) channels. The arrow and vertical bar represents time of α-KTX-5 family scaffold, which serves as "poreplungers".
intracellular injection and period of toxin perfusion, respectively.
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preclinical and formal safety trials with this (α -adrenoceptor and muscarinic ACh Conantokin-G, a 17 amino acid peptide isolated synthetic conopeptide. According to Metabolic receptor antagonism), and thus may be useful from Conus geographus selectively inhibits Pharmaceuticals, preclinical trials show almost clinically.39,40 NR2B, while its related isoform, Conantokin-T, full relief of chronic pain with no apparent side 21 amino acids long, isolated from Conus tulipa, effects and Phase I clinical trials are set to begin Neurotensin Receptor Agonist inhibits both NR2B and NR2A receptors.8,47 in early 2005.
Both Con-G and Con-T lack disulfi de bonds, Contulakin-G is a novel 16-amino acid and their structural stability is due to fi ve conopeptide originally isolated from the venom Noradrenaline Transporter Inhibitors post-translationally modifi ed residues of the of the marine snail Conus geographus.41 Cognetix Noradrenaline (or norepinephrine) (NE) nonstandard amino acid γ-carboxyglutamate Inc. is developing Contulakin-G (CGX-1160) for the participates in a number of biological pathways (Gla).48,49 Cognetix Inc. is currently developing short-term management of post-operative pain. including the regulation of mood and sleep, conantokin-G synthetic derivative (CGX-1007) CGX-1160 interacts with the neurotensin expression of behavior, alertness and arousal. as an anti-nociceptive drug and for control of receptor 1 with 100-fold less potency (than In episodes of pain, the elevation of NE levels seizures in intractable epilepsy, and is currently neurotensin), but is 100-fold more potent as an in the spinal cord results in an inhibition of pain in Phase II clinical trials.43 analgesic, suggesting additional modes of action messages. The norepinephrine transporter (NET) besides NT binding.1 CGX-1160 has completed returns noradrenaline to the synapses. early Phase I safety studies in humans and has demonstrated effi cacy in a broad range of Among the A- super-family of conotoxins, the According to the Epilepsy Foundation of America, preclinical models of acute and chronic pain. ρ- and χ-Conotoxins are known to modulate the an estimated 1% of the total population suffers α -adrenorecetor and neuronal noradrenaline from epilepsy and seizures, affl icting more than NMDA Receptor Antagonist transporter, exemplifi ed by the two Conotoxins 2.3 million Americans, with combined direct and ρTIA and χMrlA isolated from Conus tulipa and Glutamate is the major excitatory indirect costs to the American economy of $12.5 Conus marmoreus, respectively.
billion. Total market volume of anti-epileptic neurotransmitter in the mammalian CNS. Upon release from presynaptic terminals, glutamate drugs reaches $1.9 billion a year worldwide, with The synthetic χMrlA, termed Xen2174, acts by binds to postsynaptic ionotrophic receptors a 5% annual growth rate.
selectivity binding to NET and abolishing its NMDA, kainite and AMPA. Glutamate acting on ability to transport NE from the synapse back NMDA receptors is responsible for the initiation of NMDA Receptor Antagonist into the nerve ending. Xen2174, developed by CNS sensitization and hyperexcitability of spinal NMDA receptors have been shown to participate Xenome Ltd, has recently entered Phase I clinical cord neurons upon nerve injury.42,43 Non-specifi c in a number of CNS malfunctions. CGX-1007 (see trials (intrathecal) for relieving nociceptive NMDA antagonists relieve injury–induced pain, above) is currently in Phase II clinical trials as and neuropathic pain, while ρTIA is currently in but have pronounced side effects.43,44,45,50 an anticonvulsant and for intractable epilepsy preclinical trials.3 Preclinical trial of Xen2174 (when delivered directly into the central nervous in experimental animal pain models show no Conantokins were identifi ed as a group of system). The Phase I, randomized, double blind, side effects and a high therapeutic index. Both peptides that competitively inhibit glutamate placebo-controlled trial involved intravenous ρTIA and χMrlA lack the common and often activation, especially through NR2B or NR2B delivery of single, escalating doses of CGX-1007 therapeutically limiting pharmacology of α - and NR2A subunits of NMDA receptors, and can in healthy, normal subjects to determine safety adrenoceptor antagonists (α -adrenoceptor discriminate between the different NMDA receptor of the compound when administered to the and Na+ channel inhibition) and NET inhibitors types in the human brain.7,8,43,46 systemic circulation. The results of the Phase I rStromatoxin-1A Novel Blocker of K 2 K+ Channels Stromatoxin-1 (ScTx-1) (#RTS-350) is a 34 amino acid peptide that belongs to the structural inhibitor cysteine knot spider peptide family. Electrophysiological recordings on COS cell expressing voltage-dependent K+ channels show that this toxin acts as a gating modifier. Native ScTx-1 blocked K 2.1, K 2.2, K 2.1/9.3 and K 4.2, with IC of 12.7nM, 21.4nM, 7.2nM and 1.2nM, respectively. No activity on K 4.1 and K 4.3 was observed.
Model structure of ScTx-1, based on its homology to Hanatoxin1 (1DLH), SGTx (1LA4) and ω-Grammotoxin SIA (1KOZ). This class of peptides possesses the scaffold of structural inhibitor cysteine knot spider peptide family, which was shown to function as a gating modifi er.
rStromatoxin-1 (#RTS-350) inhibition of K 2.1 channels expressed in Xenopus oocytes. Left: current responses to 100 ms depolarization to 0 mV from holding potential of –100 mV, delivered every 10 seconds before (red) and during application of 670 nM rScTx-1. Right: time course of amplitude inhibition. The horizontal bars indicate the periods of rScTx-1 perfusion. Modulator No.19 Spring 2005 Modulator No.19 Spring 2005 trial demonstrated that CGX-1007 was safe, with jaracusa) developed by Bristol-Myers Squibb.52 from the venom of the Malaysian pit viper no clinically remarkable drug-related adverse (Agkistrodon rhodostoma) is in late Phase III trials experiences observed. Recently it was shown Platelet Aggregation and Blood Clotting by Neurobiological Industries Inc. for use in the that although considered NR2B-specifi c, CGX- Inhibitors (inhibitors of platelet glycoprotein IIb/ treatment of heparin-induced thrombocytopenia 1007 is less specifi c or acts differently, than the (defi cit of platelets). Researchers found that investigational CI-1041 compound, in corneal Schering-Plough and Millennium Pharmaceuticals blood failed to clot in animals bitten by these kindled rats and in an NMDA receptor mediated have been granted FDA approval for Integrilin® snakes. ViprinexTM removes fi brinogen from the excitatory postsynaptic currents model (N- (Eptifi batide), a synthetic analog of barbourin, blood, improving blood fl ow, a useful property for the treatment of severe cardiovascular that also has potential for the treatment of stroke.
Stroke, Neuroprotection and diseases, namely, anticoagulation in patients with acute coronary syndrome (ACS) and for Fibrin Thrombolytic Agent Cardiovascular Disorders patients without ACS undergoing percutaneous Nuvelo Inc. is currently evaluating Alfi meprase, a coronary intervention (angioplasty). Integrilin® synthetic version of fi brolase, a protein isolated is a heptapeptide derived from a protein found in Stroke and myocardial ischemia affect more than from the venom of the southern copperhead viper the venom of the southeastern pygmy rattlesnake 65 million people in the United States and are (Agkistrodon contortrix), as an anticoagulant for (Sistrurus miliarius barbouri ).53 Integrilin® acts the leading cause of death. Stroke is the leading the treatment of ischemic stroke and catheter as a parenteral platelet receptor glycoprotein cause of adult disability. Each year more than occlusion. Alfi meprase, now in Phase II, was IIb IIIa (GPIIb-IIIa) inhibitor and blocks platelet 700,000 Americans suffer a stroke, and one shown to directly degrade fi brin, producing a aggregation, a crucial event in thrombosis. in fi ve of them die. The total market volume of rapid dissolution of blood clots. Furthermore, cardiovascular disorders drugs is estimated to be Alfi meprase is currently in Phase II for catheter Aggrastat® (Tirofi ban), developed by Merck, around $60 billion a year worldwide.51 is also a GPIIb-IIIa inhibitor, however this drug was modeled on the structure of Echistatin, Angiotensin Converting Enzyme (ACE) Thrombin Inhibitors a derivative of the anticoagulant found in the ACE is an essential enzyme required for venom of the African saw-scaled viper (Echis AstraZeneca is seeking FDA approval for ExantaTM production of angiotensin, associated with carinatus). Aggrastat® was the fi rst GPIIb-IIIa (Ximelagatran) for treatment of patients with hypertension due to vasoconstriction. Anti- inhibitor to be launched, but it is only approved atrial fi brillation and patients at risk for blood hypertensive effect is achieved by inhibiting ACE. for use with heparin and aspirin for the treatment clots. The orally active thrombin inhibitor was Capoten® (captopril) is a small molecular mimetic designed based on a cobra venom peptide. It compound derived from a toxin found in the is already on sale in Europe as a treatment to venom of the Brazilian arrowhead viper (Bothrops ViprinexTM (Ancrod), a compound isolated prevent blood clotting after orthopedic surgery.55 rSlotoxinA Novel Blocker of K 1.1 (BK ) K+ Channels rSlotoxin (#RTS-410) is a 37 amino acid peptide toxin isolated from Centruroides noxius. Native Slotoxin blocks the Maxi K+ (BK or slo, KCNMA1, K 1.1) channels. Slotoxin blocks differentially channels formed by the α1 subunit alone and channels formed by the α1 combined with auxiliary β subunits. In Xenopus oocytes expressing hSlo (α1 alone), K was calculated to be 1.5 nM and the block is complete and reversible. With the additional co-expression of either the β1 or β4 subunits, the block becomes irreversible or causes the channel to be almost insensitive to the Model structure of Slotoxin, based on its Homology to Hongotoxin (1hlyA). This class of peptides possesses the α-KTX-1 family scaffold, which serves as "pore-plungers".
The effect of 100 nM rSlotoxin (#RTS-410) on heterologously expressed BK currents (mSlo, RNA injected to Xenopus oocytes). Lower: time course of current amplitude changes upon application of the toxin (bars represent the time of toxin perfusionUpper: An example of current response to 100 ms depolarization to +20 mV (from holding potential of –100 mV) before (red) and during (black) perfusion of 100 nM toxin.
Modulator No.19 Spring 2005 Modulator No.19 Spring 2005 Delucemine (NPS 1506) is a compound being Chlorotoxin is a 36-amino acid peptide that developed by NPS Pharmaceuticals as a means Current estimates by the American Cancer was originally isolated from the venom of the of protecting brain cells in ischaemia victims. Society indicate that approximately 1.3 million Leiurus quinquestriatus scorpion as a putative Its structure was based on a spider venom individuals in the U.S. were diagnosed with Cl- channel inhibitor.58 It was later found that toxin.56,57 Phase I clinical trials with delucemine cancer and there were about 500,000 cancer Chlorotoxin could inhibit invasiveness of glioma are currently underway in patients suffering from related deaths in 2002. Approximately $10 billion cells in vitro. This inhibition was attributed to the stroke and acute depression. NPS 1506 blocks is spent on cancer drugs annually and cancer drug ability of Chlorotoxin to block an unidentified NMDA receptors on neurons, thus preventing expenditures account for roughly 8% of total U.S. Cl- channel that was putatively involved in the excessive Ca2+ influx during ischaemia. process of regulatory volume decrease, a key step Synthetic/modified venom peptides Voltage-Gated Ca2+ Severe chronic inflammatory and Conus magus neuropatic pain associated with (SNX-111, Ziconotide) Voltage-Gated Ca2+ Severe chronic pain associated Amrad Corporation ω-Conotoxin CVID Conus catus Chronic neuropathic pain, and α-Conotoxin Vc1.1 Conus victoriae Neuronal Nicotinic acceleration of recovery of injured Preclinical Acetylcholine Receptors χ-Conotoxin χMrlA Conus marmoreus Nociceptive and neuropathic pain transporter (NET) Conus tulipa α -adrenoreceptor Nociceptive and neuropathic pain Short-term management of post- Cognetix Inc.
Conus geographus Neurotensin Receptor agonist Nociceptive pain and control of Cognetix Inc.
Conus tulipa seizures in intractable epilepsy TransMolecular Inc.
Chronic monotherapy and pharmaceutical sensitizer co- TransMolecular Inc.
administered drug cocktails for Southern copperhead viper Thrombolytic agent and catheter occlusion Pivotal Biosciences/ Southern copperhead viper University of Southern Gila monster (Heloderma Type-2 diabetes and related Amylin Pharmaceuticals Glucagon-like peptide-1 metabolic disorders Peptomimetics or small molecular weight derivatives Brazilian arrowhead viper Angiotensin Converting Bristol-Myers Squibb Capoten® (Captopril) Schering-Plough Millennium Acute coronary syndrome Southeastern pygmy Platelet glycoprotein IIb/ (ACS) and for patients without rattlesnake (Sistrurus (COR Therapeutics) IIIa receptor Inhibitors ACS undergoing percutaneous coronary intervention Approved for use Platelet glycoprotein IIb/ with heparin and Aggrastat® (Tirofiban) African saw-scaled viper Acute coronary syndrome (ACS) IIIa receptor Inhibitors Neurobiological Industries Malaysian pit viper ViprinexTM (Ancrod) thrombocytopenia Thrombin inhibitors Atrial fibrillation and blood clotting after orthopedic surgery ( ) Protection of brain cells from NPS Pharmaceuticals Delucemine (NPS 1506) Spider venom toxin Modulator No.19 Spring 2005 Modulator No.19 Spring 2005 in cell migration. Interestingly, Chlorotoxin was the venom of the southern copperhead viper Furthermore, GLP-1 like peptides share structural found to bind specifi cally to glioma cell lines and (Agkistrodon contortrix), binds to integrins on homology to α-Latrotoxin, isolated from the primary cultures, but not to normal brain cells.59,60 the surface of cancer cells and inhibits tumor venom of the black widow spider and might Positive staining towards the labled-Chlorotoxin growth and metastasis, while no cytotoxic effect have potential in the treatment of Alzheimer's was found in other solid tumor cell lines, on human breast cancer cells is observed.62 PB2 including non-small cell lung carcinoma, breast, (Contortrostatin), is cytostatic, ‘freezing' tumor prostate, melanoma, and colon cancers. Recent cells rather than killing them.63 It is presently in Immunosuppressants and studies have shown that contrary to the original preclinical research for the treatment of breast hypothesis, the specifi c target of Chlorotoxin cancer by Pivotal Biosciences and the University Autoimmune Disorders on the surface of glioma cells might be matrix of Southern California.
metalloproteinase-2 (MMP-2) protein and not a The existence and participation of the Cl- channel.61 Recently TransMolecular Inc. has voltage-dependent K+ channel K 1.3 and the initiated Phase II clinical trials with its iodinated Ca2+-activated intermediate K+ channel IKCa1 Chlorotoxin derivate TM-601(131I-Chlorotoxin) Glucagon-Like Peptide-1 (GLP-1) (K 3.1) in T-lymphocyte activation is well for the treatment of brain tumors. TM-701, a established.1,9 Furthermore, a marked elevation Glucagon-Like Peptide-1 is an insulinotopic derivative of TM-601, shares the same mechanism of K 1.3 is reported in encephalitogenic T-cells, hormone secreted from endocrine cells of the of action, but is used without a radioisotope. TM- which mediate demyelination of axons in the small and large intestine in a nutrient-dependent 701 is being developed as a chronic monotherapy brain and spinal cord, the hallmark of multiple manner. GLP-1 stimulates insulin secretion and and pharmaceutical sensitizer when administered sclerosis.66 The use of specifi c blockers for modulates gastric emptying to slow the entry of with commonly used drug cocktails for treating K channels might have therapeutic potential ingested sugars into the bloodstream. The GLP- for treatment of autoimmune disease, and as cancer and is currently in preclinical trials. Other 1 related peptide is a peptide initially derived immunosuppressents for transplantations. In derivatives of TM-601 are being tested for use in from the salivary secretions of the Gila monster in vitro studies, the use of peptidyl toxins has in vivo imaging and diagnostic test kits.
(Heloderma suspectum), a large venomous indicated that blockage of K 1.3 inhibits T-cell lizard. Amylin Pharmaceuticals is developing activation, suggesting that K 1.3 may be a target a synthetic version of Exenatide (synthetic for immunosuppression.9 This concept was Integrins are a family of cell surface proteins, exendin-4), a 39 amino acid peptide, currently in verifi ed by in vivo experiments on peripheral T- found on many cell types that mediate Pre-Phase III for use in treating type-2 diabetes cells of mini-swine using Margatoxin as specifi c interactions between cells, and between and related metabolic disorders. Diabetic animal K 1.3 toxin.67,68 Side effects of Margatoxin cells and their surroundings. Specifi c integrin models have demonstrated that Exenatide is administration have been observed, mainly in isoforms are upregulated during tumor growth.71 biologically active when administered via oral, the enteric nervous system which is expected Contortrostatin, a protein extracted from sublingual, pulmonary, tracheal and nasal routes. for all non-specifi c K 1.3 toxins.1,9 Furthermore, Anti-K 1.3 Extracellular and K 1.3 - Extracellular-FITC K 1.3 belongs to the Shaker family of voltage- central role of K 1.3 in regulating the initiation of an channel. The antibody can be obtained in a purified dependent K+ channels. The channel is widely immune response, the channel has been recognized as format (#APC-101) or labeled with fluorescein expressed in the brain, lung and osteoclasts and a potential target for immunosuppressant drugs. The (#APC-101F). The antibodies have been tested in several cell populations of hematopoietic origin. central role of K 1.3 in immune system cells created a successfully in flow cytometry, immunocytochemistry It is in these cells (particularly T lymphocytes) that real need for a specific antibody that would be able to and western blot applications.
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Modulator No.19 Spring 2005 Modulator No.19 Spring 2005


J Bioenerg Biomembr (2009) 41:85–94DOI 10.1007/s10863-009-9199-5 Purinergic signalling in rat GFSHR-17 granulosa cells:an in vitro model of granulosa cells in maturing follicles Willem Bintig & Judith Baumgart & Wilhelm J. Walter &Alexander Heisterkamp & Holger Lubatschowski &Anaclet Ngezahayo Received: 18 October 2008 / Accepted: 21 January 2009 / Published online: 4 February 2009

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