A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases

Harunur Rashid, Redwan Huq, Mark R Tanner, Sandeep Chhabra, Keith K Khoo, Rosendo Estrada, Vikas Dhawan, Satendra Chauhan, Michael William Pennington, Christine Beeton, Serdar Kuyucak, Raymond Stanley Norton

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Abstract

HsTX1 toxin, from the scorpion Heterometrus spinnifer, is a 34-residue, C-terminally amidated peptide cross-linked by four disulfide bridges. Here we describe new HsTX1 analogues with an Ala, Phe, Val or Abu substitution at position 14. Complexes of HsTX1 with the voltage-gated potassium channels Kv1.3 and Kv1.1 were created using docking and molecular dynamics simulations, then umbrella sampling simulations were performed to construct the potential of mean force (PMF) of the ligand and calculate the corresponding binding free energy for the most stable configuration. The PMF method predicted that the R14A mutation in HsTX1 would yield a > 2a ?...kcal/mol gain for the Kv1.3/Kv1.1 selectivity free energy relative to the wild-type peptide. Functional assays confirmed the predicted selectivity gain for HsTX1[R14A] and HsTX1[R14Abu], with an affinity for Kv1.3 in the low picomolar range and a selectivity of more than 2,000-fold for Kv1.3 over Kv1.1. This remarkable potency and selectivity for Kv1.3, which is significantly up-regulated in activated effector memory cells in humans, suggest that these analogues represent valuable leads in the development of therapeutics for autoimmune diseases.
Original languageEnglish
Pages (from-to)1 - 9
Number of pages9
JournalScientific Reports
Volume4
Issue number4509
DOIs
Publication statusPublished - 2014

Cite this

Rashid, Harunur ; Huq, Redwan ; Tanner, Mark R ; Chhabra, Sandeep ; Khoo, Keith K ; Estrada, Rosendo ; Dhawan, Vikas ; Chauhan, Satendra ; Pennington, Michael William ; Beeton, Christine ; Kuyucak, Serdar ; Norton, Raymond Stanley. / A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases. In: Scientific Reports. 2014 ; Vol. 4, No. 4509. pp. 1 - 9.
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title = "A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases",
abstract = "HsTX1 toxin, from the scorpion Heterometrus spinnifer, is a 34-residue, C-terminally amidated peptide cross-linked by four disulfide bridges. Here we describe new HsTX1 analogues with an Ala, Phe, Val or Abu substitution at position 14. Complexes of HsTX1 with the voltage-gated potassium channels Kv1.3 and Kv1.1 were created using docking and molecular dynamics simulations, then umbrella sampling simulations were performed to construct the potential of mean force (PMF) of the ligand and calculate the corresponding binding free energy for the most stable configuration. The PMF method predicted that the R14A mutation in HsTX1 would yield a > 2a ?...kcal/mol gain for the Kv1.3/Kv1.1 selectivity free energy relative to the wild-type peptide. Functional assays confirmed the predicted selectivity gain for HsTX1[R14A] and HsTX1[R14Abu], with an affinity for Kv1.3 in the low picomolar range and a selectivity of more than 2,000-fold for Kv1.3 over Kv1.1. This remarkable potency and selectivity for Kv1.3, which is significantly up-regulated in activated effector memory cells in humans, suggest that these analogues represent valuable leads in the development of therapeutics for autoimmune diseases.",
author = "Harunur Rashid and Redwan Huq and Tanner, {Mark R} and Sandeep Chhabra and Khoo, {Keith K} and Rosendo Estrada and Vikas Dhawan and Satendra Chauhan and Pennington, {Michael William} and Christine Beeton and Serdar Kuyucak and Norton, {Raymond Stanley}",
year = "2014",
doi = "10.1038/srep04509",
language = "English",
volume = "4",
pages = "1 -- 9",
journal = "Scientific Reports",
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Rashid, H, Huq, R, Tanner, MR, Chhabra, S, Khoo, KK, Estrada, R, Dhawan, V, Chauhan, S, Pennington, MW, Beeton, C, Kuyucak, S & Norton, RS 2014, 'A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases', Scientific Reports, vol. 4, no. 4509, pp. 1 - 9. https://doi.org/10.1038/srep04509

A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases. / Rashid, Harunur; Huq, Redwan; Tanner, Mark R; Chhabra, Sandeep; Khoo, Keith K; Estrada, Rosendo; Dhawan, Vikas; Chauhan, Satendra; Pennington, Michael William; Beeton, Christine; Kuyucak, Serdar; Norton, Raymond Stanley.

In: Scientific Reports, Vol. 4, No. 4509, 2014, p. 1 - 9.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases

AU - Rashid, Harunur

AU - Huq, Redwan

AU - Tanner, Mark R

AU - Chhabra, Sandeep

AU - Khoo, Keith K

AU - Estrada, Rosendo

AU - Dhawan, Vikas

AU - Chauhan, Satendra

AU - Pennington, Michael William

AU - Beeton, Christine

AU - Kuyucak, Serdar

AU - Norton, Raymond Stanley

PY - 2014

Y1 - 2014

N2 - HsTX1 toxin, from the scorpion Heterometrus spinnifer, is a 34-residue, C-terminally amidated peptide cross-linked by four disulfide bridges. Here we describe new HsTX1 analogues with an Ala, Phe, Val or Abu substitution at position 14. Complexes of HsTX1 with the voltage-gated potassium channels Kv1.3 and Kv1.1 were created using docking and molecular dynamics simulations, then umbrella sampling simulations were performed to construct the potential of mean force (PMF) of the ligand and calculate the corresponding binding free energy for the most stable configuration. The PMF method predicted that the R14A mutation in HsTX1 would yield a > 2a ?...kcal/mol gain for the Kv1.3/Kv1.1 selectivity free energy relative to the wild-type peptide. Functional assays confirmed the predicted selectivity gain for HsTX1[R14A] and HsTX1[R14Abu], with an affinity for Kv1.3 in the low picomolar range and a selectivity of more than 2,000-fold for Kv1.3 over Kv1.1. This remarkable potency and selectivity for Kv1.3, which is significantly up-regulated in activated effector memory cells in humans, suggest that these analogues represent valuable leads in the development of therapeutics for autoimmune diseases.

AB - HsTX1 toxin, from the scorpion Heterometrus spinnifer, is a 34-residue, C-terminally amidated peptide cross-linked by four disulfide bridges. Here we describe new HsTX1 analogues with an Ala, Phe, Val or Abu substitution at position 14. Complexes of HsTX1 with the voltage-gated potassium channels Kv1.3 and Kv1.1 were created using docking and molecular dynamics simulations, then umbrella sampling simulations were performed to construct the potential of mean force (PMF) of the ligand and calculate the corresponding binding free energy for the most stable configuration. The PMF method predicted that the R14A mutation in HsTX1 would yield a > 2a ?...kcal/mol gain for the Kv1.3/Kv1.1 selectivity free energy relative to the wild-type peptide. Functional assays confirmed the predicted selectivity gain for HsTX1[R14A] and HsTX1[R14Abu], with an affinity for Kv1.3 in the low picomolar range and a selectivity of more than 2,000-fold for Kv1.3 over Kv1.1. This remarkable potency and selectivity for Kv1.3, which is significantly up-regulated in activated effector memory cells in humans, suggest that these analogues represent valuable leads in the development of therapeutics for autoimmune diseases.

UR - http://www.nature.com/srep/2014/140328/srep04509/pdf/srep04509.pdf

U2 - 10.1038/srep04509

DO - 10.1038/srep04509

M3 - Article

VL - 4

SP - 1

EP - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 4509

ER -