Chemical synthesis and characterization of ShK toxin: a potent potassium channel inhibitor from a sea anemone

Pennington, Michael W.; Byrnes, M.; Zaydenberg, I.; Khaytin, Ilya; Chastonay, J. de; Krafte, Douglas S.; Hill, Robert E.; Mahnir, Vladimir M.; Volberg, Walter A.; Gorczyca, William P.; Kem, William R.

doi:10.1111/j.1399-3011.1995.tb01068.x

Cited by 96 publications

(47 citation statements)

References 15 publications

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“…Indeed, a derivative of the sea anemone toxin ShK, which selectively targets the K V 1.3 isoform, is currently in human clinical trials for treatment of multiple sclerosis. [94][95][96] Preclinical studies for kconopeptide PVIIA, which selectively targets Shaker K V channels, demonstrated that this conopeptide is cardioprotective in animal models. Terlau and co-workers showed that this peptide is state selective, and that channels inhibited with k-PVIIA were also inhibited in the progression to a slow inactivated state.…”

Section: Generation Of Peptide Diversitymentioning

confidence: 98%

CHAPTER 6. The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications

Teichert

Olivera²,

McIntosh³

et al. 2015

Drug Discovery

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Section: Generation Of Peptide Diversitymentioning

confidence: 98%

CHAPTER 6. The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications

Teichert

Olivera²,

McIntosh³

et al. 2015

Drug Discovery

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“…With respect to the Kv1.3 channel, many structurally diverse peptide toxins, such as ChTX (11,12), ShK (13,14), and OSK1 (15), have been identified. Although these inhibitors can block potassium currents at nM or pM concentrations, they lack sufficient specificity to distinguish between Kv1.3 and other related Kv1.x channels.…”

mentioning

confidence: 99%

Structural Basis of a Potent Peptide Inhibitor Designed for Kv1.3 Channel, a Therapeutic Target of Autoimmune Disease

Han¹,

Yi²,

Yin³

et al. 2008

Journal of Biological Chemistry

128

186

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The potassium channel Kv1.3 is an attractive pharmacological target for immunomodulation of T cell-mediated autoimmune diseases. Potent and selective blockers of Kv1.3 are potential therapeutics for treating these diseases. 28 and His 33 of ADWX-1 locate right above the selectivity filter-S6 linker of Kv1.3. Together, our data indicate that the specific ADWX-1 peptide would be a viable lead in the therapy of T cell-mediated autoimmune diseases, and the successful design of ADWX-1 suggests that rational design based on the structural model of the peptide-channel complex should accelerate the development of diagnostic and therapeutic agents for human channelopathies.

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“…Sea anemones contain a family of polypeptide toxins that block potassium channels, the first representative of which to be isolated and characterized was ShK toxin, from Stichodactyla helianthus (1,2). Its solution structure, determined by NMR spectroscopy (3,4), consists of two short ␣-helices encompassing residues 14 -19 and 21-24, and an N terminus with an extended conformation up to residue 8, followed by a pair of interlocking turns that resembles a 3 10 -helix.…”

mentioning

confidence: 99%

The D-Diastereomer of ShK Toxin Selectively Blocks Voltage-gated K+ Channels and Inhibits T Lymphocyte Proliferation

Beeton

Smith

Sabo

et al. 2008

Journal of Biological Chemistry

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The polypeptide toxin ShK is a potent blocker of Kv1.3 potassium channels, which are crucial in the activation of human effector memory T cells (T EM ); selective blockers constitute valuable therapeutic leads for the treatment of autoimmune diseases mediated by T EM cells, such as multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. The critical motif on the toxin for potassium channel blockade consists of neighboring lysine and tyrosine residues. Because this motif is sufficient for activity, an ShK analogue was designed based on D-amino acids. D-Allo-ShK has a structure essentially identical with that of ShK and is resistant to proteolysis. It blocked Kv1.3 with K d 36 nM (2,800-fold lower affinity than ShK), was 2-fold selective for Kv1.3 over Kv1.1, and was inactive against other K ؉ channels tested. D-Allo-ShK inhibited human T EM cell proliferation at 100-fold higher concentration than ShK. Its circulating half-life was only slightly longer than that of ShK, implying that renal clearance is the major determinant of its plasma levels. D-AlloShK did not bind to the closed state of the channel, unlike ShK. Models of D-allo-ShK bound to Kv1.3 show that it can block the pore as effectively as ShK but makes different interactions with the vestibule, some of which are less favorable than for native ShK. The finding that an all-D analogue of a polypeptide toxin retains biological activity and selectivity is highly unusual. Being resistant to proteolysis and nonantigenic, this analogue should be useful in K ؉ channel studies; all-D analogues with improved Kv1.3 potency and specificity may have therapeutic advantages.

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Chemical synthesis and characterization of ShK toxin: a potent potassium channel inhibitor from a sea anemone

Cited by 96 publications

References 15 publications

CHAPTER 6. The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications

CHAPTER 6. The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications

Structural Basis of a Potent Peptide Inhibitor Designed for Kv1.3 Channel, a Therapeutic Target of Autoimmune Disease

The D-Diastereomer of ShK Toxin Selectively Blocks Voltage-gated K+ Channels and Inhibits T Lymphocyte Proliferation

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