Venom Peptides and Their Mimetics As Potential Drugs
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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. Introduction Pain channels has been established13 (please refer to the article “Contribution of Ion Channels in Pain Sensation” in this Modulator issue). Pain A large number of organisms produce and secrete Recurrent pain was recently termed the “silent signals can be blocked at a number of sites along venoms to defend themselves and to capture epidemic”, since one out of six people in the the pain pathway (See Figure). The large list of prey. Venom is a rich source of biochemically western world suffers from pain, costing the neurotransmitters and receptors identified along active enzymes, proteins, peptides and low American public alone approximately $100 the pain pathway indicate that there may be many molecular weight substances. Toxins isolated billion each year in health care, compensation, therapeutic possibilities for the pharmacological from the venom either inhibit or activate a and litigation.11,12 Chronic pain is associated control of the transmission of nociceptive vast number of targets such as ion channels, with conditions such as back injury, migraine information to the brain. acetylcholine receptors, acetylcholinesterase, headaches, arthritis, herpes zoster, diabetic membranes, coagulant/anticoagulant pathways, neuropathy, temporomandibular joint syndrome, Voltage-Gated Ca2+ Channels (VGCC) and metalloproteases, with high selectivity and cancer. Effective treatment options are and affinity. They can be roughly divided into limited to opioids (morphine and related drugs) Cav2.2 (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 CaV2.2 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 CaV2.2 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 3 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 3 as possible therapeutic targets.14,19,20 toxin activity have been identified, thus enabling 2 the rational design of small molecular weight compounds or peptomimetics. 1- Voltage-Gated Na+ Channels 3 2- Voltage-Gated Ca2+ Channels The pharmaceutical industry has recognized 1 3- Neuronal Nicotinic Acetylcholine the enormous potential inherent in these venom Receptors peptides and has begun to exploit the selectivity Noradrenaline Transporter 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 1-10). possible localization of the pain pathway targets are illustrated above. 14 15 Modulator No.19 Spring 2005 www.alomone.com Modulator No.19 Spring 2005 www.alomone.com 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 2+ + + and snakes. The most selective inhibitors of N- with D-amino acids having an IC50 of ~20 µM and Ca , 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 21 28 selective blocker of N-type VGCC. A synthetic IC50 of ~3 µM. 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 NaV1.8 and NaV1.9 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 32 VGCC associated with transmitter release from due to NaV1.4 channel inhibition. 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,