Ziconotide: Neuronal Calcium Channel Blocker for Treating Severe Chronic Pain

Elan Pharmaceuticals, Inc., 7475 Lusk Boulevard, San Diego, CA 92121, USA.
Current Medicinal Chemistry (Impact Factor: 3.85). 01/2005; 11(23):3029-40. DOI: 10.2174/0929867043363884
Source: PubMed


Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.

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    • "However, there are examples where the therapeutic potential of a toxin has been realized prior to resolution of the structure of the target ion channel, such as Prialt (ziconotide), a naturally occurring peptide conotoxin from the cone snail Conus magus. The high selectivity of this toxin in blocking N-type calcium channels involved in excitatory neurotransmitter release from primary afferent nerve terminals enabled registration as a drug for treatment of pain (McIntosh et al. 1982; Miljanich 2004). Another heralded achievement was the engineering of ShK 192, a highly active analogue of the naturally occurring toxin peptide ShK-L5 from the sea anemone Stichodactyla helianthus, to blocking of K v 1.3 channels and raising a therapeutic potential in autoimmune diseases mediated by effector memory T cells (Pennington et al. 2009). "
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    ABSTRACT: Scorpion alpha and beta toxins interact with voltage-gated sodium channels (Navs) at two pharmacologically distinct sites. Alpha toxins bind at receptor site 3 and inhibit channel inactivation, whereas beta toxins bind at receptor site 4 and shift the voltage-dependent activation toward more hyperpolarizing potentials. The two toxin classes are subdivided to distinct pharmacological groups according to their binding preferences and competition for receptor sites at Nav subtypes. To elucidate the surface of interaction of the two toxin classes with Navs and clarify the molecular basis of varying toxin preferences, an efficient expression system was established. Mutagenesis accompanied by toxicity, binding, and electrophysiological assays, in parallel to determination of the three-dimensional structure using NMR and X-ray crystallography, uncovered the bioactive surfaces of toxin representatives of all pharmacological groups. Exchange of external loops between channels that exhibit marked differences in sensitivity to various toxins accompanied by point mutagenesis highlighted channel determinants that play a role in toxin selectivity. These data were used in further mapping of the brain channel rNav1.2a receptor sites for the beta-toxin Css4 (from Centruroides suffusus suffusus) and the alpha-toxin Lqh2 (from Leiurus quinquestriatus hebraeus). On the basis of channel mutations that affected Css4 activity, the known structure of the toxin and its bioactive surface, and using the structure of a potassium channel as template, a structural model of Css4 interaction with the gating module of domain II was constructed. This initial model was the first step in the identification of part of receptor site 4. In parallel, a swapping and a mutagenesis approach employing the rNav1.2a mammalian and DmNav1 insect Navs and the toxin Lqh2 as a probe were used to search for receptor site 3. The channel mapping along with toxin dissociation assays and double-mutant cycle analyses using toxin and channel mutants identified the gating module of domain IV as the site of interaction with the toxin core domain, thus describing the docking orientation of an alpha toxin at the channel surface.
    Scorpion Venoms, 01/2015: pages 471-491; , ISBN: 978-94-007-6403-3
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    • "conotoxins) or, in general, disrupting critical biochemical signalling networks within the prey's body [61], low doses of these peptides can actually counteract disturbances from diverse disorders. Accordingly, toxic peptides may aid in treating pain [41], neurological and cardiovascular diseases, diabetes and cancer [32]. A prominent example is the type 2 diabetes drug Exenatide, a synthetic version of a glucagon-like peptide-1 analogue found in the venom of the Gila monster Heloderma suspectum [7]. "
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    ABSTRACT: This minireview touches upon the challenges and opportunities peptides experience on the track to become an approved pharmaceutical. Peptide attributes originally considered troublesome with respect to drug development may now turn out to be more convenient rather than unfavourable. Besides characteristic high target affinity, biological peptides often exhibit higher than expected stability. Clearly natural selective pressure has optimised these biomolecules beyond what can be anticipated solely on the basis of their chemical nature. This concept is gradually finding its way into the pharma and biotech industry, as illustrated by a rise in medicinal peptide patent applications and developmental work.
    EuPA Open Proteomics 09/2014; 4. DOI:10.1016/j.euprot.2014.05.003
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    • "Increasing the rate of species description for conoideans is crucial for two main reasons: (1) Their potential susceptibility to environmental threats, as many of them are members of coral reef communities; and (2) conoidean venoms are rich in neuropeptides that are important tools for biochemical investigations of neuronal signaling and have relevant pharmacological applications. Conoidea is one of the most promising animal groups for the discovery of novel pharmacologically active neuropeptides, as exemplified by the development of the first drug from a cone snail conopeptide, ziconotide (Prialt), which is used to alleviate chronic pain in HIV and cancer patients [28]. Traditional taxonomic approaches, based mainly on shell characters, are of little value to identify conoidean species [29], [30], and recent DNA-based taxonomic studies demonstrated that the traditional taxonomic framework of conoideans is largely inadequate [27], [31]–[33]. "
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    ABSTRACT: Devising a reproducible approach for species delimitation of hyperdiverse groups is an ongoing challenge in evolutionary biology. Speciation processes combine modes of passive and adaptive trait divergence requiring an integrative taxonomy approach to accurately generate robust species hypotheses. However, in light of the rapid decline of diversity on Earth, complete integrative approaches may not be practical in certain species-rich environments. As an alternative, we applied a two-step strategy combining ABGD (Automated Barcode Gap Discovery) and Klee diagrams, to balance speed and accuracy in producing primary species hypotheses (PSHs). Specifically, an ABGD/Klee approach was used for species delimitation in the Terebridae, a neurotoxin-producing marine snail family included in the Conoidea. Delimitation of species boundaries is problematic in the Conoidea, as traditional taxonomic approaches are hampered by the high levels of variation, convergence and morphological plasticity of shell characters. We used ABGD to analyze gaps in the distribution of pairwise distances of 454 COI sequences attributed to 87 morphospecies and obtained 98 to 125 Primary Species Hypotheses (PSHs). The PSH partitions were subsequently visualized as a Klee diagram color map, allowing easy detection of the incongruences that were further evaluated individually with two other species delimitation models, General Mixed Yule Coalescent (GMYC) and Poisson Tree Processes (PTP). GMYC and PTP results confirmed the presence of 17 putative cryptic terebrid species in our dataset. The consensus of GMYC, PTP, and ABGD/Klee findings suggest the combination of ABGD and Klee diagrams is an effective approach for rapidly proposing primary species proxies in hyperdiverse groups and a reliable first step for macroscopic biodiversity assessment.
    PLoS ONE 07/2014; 9(7):e102160. DOI:10.1371/journal.pone.0102160 · 3.23 Impact Factor
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