Chemical Engineering and Structural and Pharmacological Characterization of the α-Scorpion Toxin OD1

Durek, Thomas; Vetter, Irina; Wang, Ching-I Anderson; Motin, Leonid; Knapp, Oliver; Adams, David J.; Lewis, Richard J.; Alewood, Paul F.

doi:10.1021/cb400012k

Cited by 54 publications

(62 citation statements)

References 42 publications

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“…The pharmacological activity of SuVIA was assessed using a FLIPR Tetra fluorescent membrane potential assay as previously described [12]. (10), pH 7.4).…”

Section: (D) Flipr Membrane Potential Assaymentioning

confidence: 99%

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

et al. 2015

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Some venomous cone snails feed on small fishes using an immobilizing combination of synergistic venom peptides that target K v and Na v channels. As part of this envenomation strategy, d-conotoxins are potent ichtyotoxins that enhance Na v channel function. d-Conotoxins belong to an ancient and widely distributed gene superfamily, but any evolutionary link from ancestral worm-eating cone snails to modern piscivorous species has not been elucidated. Here, we report the discovery of SuVIA, a potent vertebrate-active d-conotoxin characterized from a vermivorous cone snail (Conus suturatus). SuVIA is equipotent at hNa V 1.3, hNa V 1.4 and hNa V 1.6 with EC 50 s in the low nanomolar range. SuVIA also increased peak hNa V 1.7 current by approximately 75% and shifted the voltage-dependence of activation to more hyperpolarized potentials from -15 mV to -25 mV, with little effect on the voltage-dependence of inactivation. Interestingly, the proximal venom gland expression and pain-inducing effect of SuVIA in mammals suggest that d-conotoxins in vermivorous cone snails play a defensive role against higher order vertebrates. We propose that d-conotoxins originally evolved in ancestral vermivorous cones to defend against larger predators including fishes have been repurposed to facilitate a shift to piscivorous behaviour, suggesting an unexpected underlying mechanism for this remarkable evolutionary transition.

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“…The pharmacological activity of SuVIA was assessed using a FLIPR Tetra fluorescent membrane potential assay as previously described [12]. (10), pH 7.4).…”

Section: (D) Flipr Membrane Potential Assaymentioning

confidence: 99%

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

et al. 2015

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“…The Na v 1.2, Na v 1.4 and Na v 1.5 sodium channels are widely used to characterize the pharmacological profiles of α-scorpion toxins [9,10,15,17,29,30,31,32,33,34]. In this work, the pharmacological effects of rBmαTX47 from the expression vector pET-14b were also examined on the rNa v 1.2, mNa v 1.4 and hNa v 1.5 channels expressed in HEK293 cells.…”

Section: Resultsmentioning

confidence: 99%

Characterization of a Novel BmαTX47 Toxin Modulating Sodium Channels: The Crucial Role of Expression Vectors in Toxin Pharmacological Activity

Tian

Hong-lian

et al. 2014

Toxins

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Long-chain scorpion toxins with four disulfide bridges exhibit various pharmacological features towards the different voltage-gated sodium channel subtypes. However, the toxin production still remains a huge challenge. Here, we reported the effects of different expression vectors on the pharmacological properties of a novel toxin BmαTX47 from the scorpion Buthus martensii Karsch. The recombinant BmαTX47 was obtained using the expression vector pET-14b and pET-28a, respectively. Pharmacological experiments showed that the recombinant BmαTX47 was a new α-scorpion toxin which could inhibit the fast inactivation of rNav1.2, mNav1.4 and hNav1.5 channels. Importantly, the different expression vectors were found to strongly affect BmαTX47 pharmacological activities while toxins were obtained by the same expression and purification procedures. When 10 µM recombinant BmαTX47 from the pET-28a vector was applied, the values of I5ms/Ipeak for rNav1.2, mNav1.4 and hNav1.5 channels were 44.12% ± 3.17%, 25.40% ± 4.89% and 65.34% ± 3.86%, respectively, which were better than those values of 11.33% ± 1.46%, 15.96% ± 1.87% and 5.24% ± 2.38% for rNav1.2, mNav1.4 and hNav1.5 channels delayed by 10 µM recombinant BmαTX47 from the pET-14b vector. The dose-response experiments further indicated the EC50 values of recombinant BmαTX47 from the pET-28a vector were 7262.9 ± 755.9 nM for rNav1.2 channel and 1005.8 ± 118.6 nM for hNav1.5 channel, respectively. Together, these findings highlighted the important role of expression vectors in scorpion toxin pharmacological properties, which would accelerate the understanding of the structure-function relationships of scorpion toxins and promote the potential application of toxins in the near future.

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“…Few reported total syntheses of protein molecules meet that standard of characterization. An example that does can be found here [5].…”

Section: Tertiary Structurementioning

confidence: 87%

Editorial overview: Synthetic Biomolecules

Kent

Alewood

2014

Current Opinion in Chemical Biology

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Chemical Engineering and Structural and Pharmacological Characterization of the α-Scorpion Toxin OD1

Cited by 54 publications

References 42 publications

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

Characterization of a Novel BmαTX47 Toxin Modulating Sodium Channels: The Crucial Role of Expression Vectors in Toxin Pharmacological Activity

Editorial overview: Synthetic Biomolecules

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