A C‐terminally amidated analogue of ShK is a potent and selective blocker of the voltage‐gated potassium channel Kv1.3

Pennington, Michael W.; Rashid, MH; Tajhya, Rajeev B.; Beeton, Christine; Kuyucak, Serdar; Norton, Raymond S.

doi:10.1016/j.febslet.2012.09.038

Cited by 41 publications

(52 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This data is then used together with docking approaches to derive a structural model of the peptide-channel complex. [3][4][5][6][7][8][9] The question is: how reliable are…”

Section: Introductionmentioning

confidence: 99%

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Deplazes

Davies

Bonvin

et al. 2015

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Peptides that bind to ion channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determination of large peptidechannel complexes using experimental methods is challenging. Thus structural models are often derived from combining experimental information with restraint-driven docking approaches. Using the complex formed by the venom peptide PcTx1 and the acid sensing ion channel (ASIC) 1a as a case study, we have examined the effect of different combinations of restraints and input structures on the statistical likelihood of (a) correctly predicting the structure of the binding interface and (b) the ability to predict which residues are involved in specific pairwise peptide-channel interactions. For this, we have analyzed over 200 000 water-refined docked structures obtained with various amounts and types of restraints of the peptidechannel complex predicted using the docking program HADDOCK. We found that increasing the number of restraints or even the use of pairwise interaction data resulted in only a modest improvement in the likelihood of finding a structure within a given accuracy. This suggests that shape complementarity and the force field make a large contribution to the accuracy of the predicted structure. The results also showed that there are large variations in the accuracy of the predicted structure depending on the precise combination of residues used as restraints. Finally, we reflect on the limitations of relying on geometric criteria such as root-mean square deviations to assess the accuracy of docking procedures. We propose that in addition to currently used measures, the likelihood of finding a structure within a given level of accuracy should be also used to evaluate docking methods.

show abstract

“…This data is then used together with docking approaches to derive a structural model of the peptide-channel complex. [3][4][5][6][7][8][9] The question is: how reliable are…”

Section: Introductionmentioning

confidence: 99%

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Deplazes

Davies

Bonvin

et al. 2015

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…Extension of the C-terminus with a residue less prone to epimerization during solid-phase peptide synthesis than cysteine 29 and substitution of the oxidizable methionine with norleucine at position 21 were investigated in combination with the lysine substitution at position 16 (Table 3). Surprisingly, addition of a C-terminal alanine to Figure S1), which are commercially available, were compared to the results reported previously for these analogs.…”

Section: Structure-function Relationships Of Kv13 Inhibitory Toxin Pmentioning

confidence: 99%

Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3

Murray¹,

Qian²,

Liu³

et al. 2015

J. Med. Chem.

View full text Add to dashboard Cite

To realize the medicinal potential of peptide toxins, naturally occurring disulfide-rich peptides, as ion channel antagonists, more efficient pharmaceutical optimization technologies must be developed. Here, we show that the therapeutic properties of multiple cysteine toxin peptides can be rapidly and substantially improved by combining direct chemical strategies with high-throughput electrophysiology. We applied whole-molecule, brute-force, structure-activity analoging to ShK, a peptide toxin from the sea anemone Stichodactyla helianthus that inhibits the voltage-gated potassium ion channel Kv1.3, to effectively discover critical structural changes for 15× selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (>1000× over Kv1.1) with picomolar functional activity in whole blood and a pharmacokinetic profile suitable for weekly administration in primates. The pharmacological potential of the optimized toxin peptide was demonstrated by potent and sustained inhibition of cytokine secretion from T cells, a therapeutic target for autoimmune diseases, in cynomolgus monkeys.

show abstract

“…ShK-Kamide is a potent blocker of Kv1.3 and, in contrast to ShK and ShK-amide, it is selective for Kv1.3. 24 To understand this selectivity, we created complexes of ShK-K-amide with Kv1.3 and Kv1.1 using docking and molecular dynamics simulations, then performed umbrella sampling simulations to construct the potential of mean force of the ligand and calculate the corresponding binding free energy for the most stable conguration. Again, the calculated values agree well with experimental results.…”

Section: How Shk Blocks K + Channelsmentioning

confidence: 99%

“…18,37 ShK-186 inhibited production of the cytokines IL-2 and IFNg by CCR7 -T EM lymphocytes more efficiently than in the case of CCR7 + naïve/T CM lymphocytes. 18 It was 17,18,24,[27][28][29][30]33,37,39,41 signicantly less effective in inhibiting production of IL-4 and TNFa. ShK-186 persistently inhibited the proliferation of CCR7 -T EM lymphocytes (IC 50 100 pM) whereas CCR7 + naïve/T CM lymphocytes were 10-fold less sensitive to the blocker at rst, and became completely resistant to ShK-186 aer their upregulation of the KCa3.1 channel.…”

Section: In Vitro Biological Activity Of Shk and Its Analoguesmentioning

confidence: 99%

CHAPTER 10. Case Study 2: Transforming a Toxin into a Therapeutic: the Sea Anemone Potassium Channel Blocker ShK Toxin for Treatment of Autoimmune Diseases

2015

Self Cite

View full text Add to dashboard Cite

A C‐terminally amidated analogue of ShK is a potent and selective blocker of the voltage‐gated potassium channel Kv1.3

Cited by 41 publications

References 30 publications

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3

CHAPTER 10. Case Study 2: Transforming a Toxin into a Therapeutic: the Sea Anemone Potassium Channel Blocker ShK Toxin for Treatment of Autoimmune Diseases

Contact Info

Product

Resources

About