Design and biological evaluation of non-peptide analogues of omega-conotoxin MVIIA

Menzler, Stefan; Bikker, Jack; Suman‐Chauhan, N.; Horwell, David C.

doi:10.1016/s0960-894x(99)00699-x

Cited by 47 publications

(26 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4B). Even though, as discussed above, the pharmacophore of -conotoxin MVIIA is discontinuous and other residues such as Lys 2 are known to be involved in the toxin-channel interaction, the rationally designed nonpeptide mimetics had IC 50 values of ϳ3 M against human N-type VGCCs (46). Although native -conotoxin MVIIA binds these channels with considerably higher subnanomolar affinity (35)(36)(37), the rationally designed mimetics nevertheless have sufficient affinity to make them desirable leads for further optimization as antinociceptive agents (46).…”

Section: Discussionmentioning

confidence: 99%

Scanning Mutagenesis of ω-Atracotoxin-Hv1a Reveals a Spatially Restricted Epitope That Confers Selective Activity against Insect Calcium Channels

Tedford

Gilles

Ménèz

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

We constructed a complete panel of alanine mutants of the insect-specific calcium channel blocker -atracotoxin-Hv1a. Lethality assays using these mutant toxins identified three spatially contiguous residues, Pro 10 , Asn 27 , and Arg 35 , that are critical for insecticidal activity against flies (Musca domestica) and crickets (Acheta domestica). Competitive binding assays using radiolabeled -atracotoxin-Hv1a and neuronal membranes prepared from the heads of American cockroaches (Periplaneta americana) confirmed the importance of these three residues for binding of the toxin to target calcium channels presumably expressed in the insect membranes. At concentrations up to 10 M, -atracotoxinHv1a had no effect on heterologously expressed rat Ca v 2.1, Ca v 2.2, and Ca v 1.2 calcium channels, consistent with the previously reported insect selectivity of the toxin. 30 M -atracotoxin-Hv1a inhibited rat Ca v currents by 10 -34%, depending on the channel subtype, and this low level of inhibition was essentially unchanged when Asn 27 and Arg 35 , which appears to be critical for interaction of the toxin with insect Ca v channels, were both mutated to alanine. We propose that the spatially contiguous epitope formed by Pro 10 , Asn 27 , and Arg 35 confers specific binding to insect Ca v channels and is largely responsible for the remarkable phyletic selectivity of -atracotoxin-Hv1a. This epitope provides a structural template for rational design of chemical insecticides that selectively target insect Ca v channels.The first peptide neurotoxins isolated from the venom of Australian funnel-web spiders (genera Atrax and Hadronyche) and shown to have selective activity against insects were members of the -atracotoxin-1 (ACTX) 1 family (1-3). These toxins comprise 36 -37 residues with six strictly conserved cysteine residues that are paired to form three disulfide bridges (4). The best studied family member, -ACTX-Hv1a, is one of the most potent insecticidal peptide toxins discovered so far (4, 5); it has proved lethal to all insect orders that have been tested, including coleopterans, dictyopterans, hemipterans, orthopterans, and refractory lepidopteran pests such as the tobacco budworm Heliothis virescens and the cotton bollworm Helicoverpa armigera (1, 2, 5).The phyletic specificity of these toxins appears to reside in their ability to block insect, but not vertebrate, voltage-gated calcium channels (2). Although nanomolar concentrations of -ACTX-Hv1a are sufficient to block high voltage-activated (HVA) calcium currents in the central nervous system of the fruit fly Drosophila melanogaster and the American cockroach Periplaneta americana (2, 5), 1 M toxin does not block HVA calcium currents in vertebrate neurons (2) and the toxin is harmless when injected subcutaneously into newborn mice (1).With the exception of the organophosphate and carbamate insecticides (which target acetylcholinesterase), the vast majority of synthetic insecticides are directed against voltagegated sodium channels, nicotinic acetylcholine receptors, or ...

show abstract

Section: Discussionmentioning

confidence: 99%

Scanning Mutagenesis of ω-Atracotoxin-Hv1a Reveals a Spatially Restricted Epitope That Confers Selective Activity against Insect Calcium Channels

Tedford

Gilles

Ménèz

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In addition to peptide toxins, only small numbers of small nonpeptide neuronal VSCC blockers, more suitable for oral therapy, have been shown to provide some degree of neuroprotection in vivo in different models of brain injury (Hicks et al, 2000;O'Neill et al, 1997), although these molecules are usually less specific (Huang et al, 1997;Schelkun et al, 1999;Hu et al, 1999;Asakura et al, 2000;Menzler et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant and neuroprotective effects of the novel calcium antagonist NP04634 on kainic acid‐induced seizures in rats

Morales-García¹,

Luna-Medina²,

Martı́nez³

et al. 2009

J of Neuroscience Research

View full text Add to dashboard Cite

Kainic acid (KA)-induced status epilepticus (SE) is a well-characterized model of excitotoxic neuronal injury. Excitotoxicity results from activation of specific glutamate receptors, with resultant elevation of intracellular Ca(2+). The CA1 and CA3 subregions of the hippocampus are especially vulnerable to KA, and this pattern of neuronal injury resembles that occurring in patients with temporal lobe epilepsy. Calcium plays an essential role in excitotoxicity, and accordingly calcium channel inhibitors have been shown to have protective effects in various experimental models of epilepsy and brain injury. Moreover, they also potentiate the antiseizure efficacy of conventional antiepileptic drugs. This study was undertaken to determine whether NP04634, a novel compound, reported as a non-L-type voltage-sensitive calcium channel (VSCC) inhibitor, could prevent the entrance in SE and the neuronal loss evoked by intraperitoneal injection of KA. Our results show that intragastrical administration of NP04634 reduced the percentage of rats that entered SE after KA injection, increased the latency of SE entry, and significantly reduced the mortality of rats that entered SE. Also, NP04634 prevented the loss of hippocampal CA1 and CA3 pyramidal neurons and reduced the gliosis induced by KA. These results point to a potential anticonvulsant and neuroprotective role for NP04634.

show abstract

“…However, the resulting nitrogen atom in the benzimidazole ring was not ideally positioned to incorporate Arg in its natural free threedimensional conformation, possibly explaining why this compound did not display the complete biological profile of HN, being an effective analgesic and anti-inflammatory agent but not protecting mice against NMDA-induced convulsions. On the other hand, o-phenylenediamine may be a scaffold that allows all pharmacophoric elements to find, in their search for global minima rather than just local minima (Menzler et al, 1998(Menzler et al, , 2000, the best fit for binding with the HN receptor(s) and thus produce mimics with larger profiles of HN activities. The construction of the o-phenylenediamine derivatives resulted from the exploration of a simple modification of the designed ␦-opioid nonpeptide ligand [(2S,3R)TMT 1 ]DPDPE to incorporate the HN pharmacophoric elements in its 1,4-piperazine backbone structure (Liao et al, 1998;Hruby, 2001).…”

Section: Discussionmentioning

confidence: 99%

Histogranin-Like Antinociceptive and Anti-Inflammatory Derivatives ofo-Phenylenediamine and Benzimidazole

Le¹,

Lemaire²,

Gilbert³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Histogranin (HN)-like nonpeptides were designed and synthesized using benzimidazole (compound 1) and o-phenylenediamine (compounds 2-7) as scaffolds for the attachment of phenolic hydroxyl and basic guanidino pharmacophoric elements present in HN. The benzimidazole derivative N-5- (2) were more potent analgesics than HN in both the mouse writhing (5.5 and 3.5 as potent as HN, respectively) and tail-flick (11.8 and 8.0 as potent as HN, respectively) pain assays. Improvements in the potencies and times of action of compound 2 in the mouse writhing test were obtained by attaching carboxyl (6) or p-Cl-benzoyl (7) groups at position 4 of the (2R) o-phenylenediamine derivative (5). In rats, compounds 2 (80 nmol i.t.), 6 (36 nmol i.t.), and 7 (18 nmol i.t.) were effective in blocking both persistent inflammatory pain in the formalin test and hyperalgesia in the complete Freund adjuvant assay. Compounds 2, 6, and 7, but not compound 1 at 10 nmol (i.c.v.) also mimicked the HN (60 nmol i.c.v.) blockade of N-methyl-D-aspartate (NMDA)-induced convulsions in mice. Finally, in primary cultures of rat alveolar macrophages, HN and compounds 1, 2, 6, and 7 (10 Ϫ8 M) significantly blocked lipopolysaccharide-induced cyclooxygenase-2 induction and prostaglandin E 2 secretion. These studies indicate that both derivatives of benzimidazole and o-phenylenediamine mimic the in vivo antinociceptive and in vitro anti-inflammatory effects of HN, but the HN protection of mice against NMDA-induced convulsions is mimicked only by the o-phenylenediamine derivatives.

show abstract

Design and biological evaluation of non-peptide analogues of omega-conotoxin MVIIA

Cited by 47 publications

References 23 publications

Scanning Mutagenesis of ω-Atracotoxin-Hv1a Reveals a Spatially Restricted Epitope That Confers Selective Activity against Insect Calcium Channels

Scanning Mutagenesis of ω-Atracotoxin-Hv1a Reveals a Spatially Restricted Epitope That Confers Selective Activity against Insect Calcium Channels

Anticonvulsant and neuroprotective effects of the novel calcium antagonist NP04634 on kainic acid‐induced seizures in rats

Histogranin-Like Antinociceptive and Anti-Inflammatory Derivatives ofo-Phenylenediamine and Benzimidazole

Contact Info

Product

Resources

About