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

• DOI: 10.1038/srep04509
• Publication Date: 2014-03-28T10:22:45Z
• Authors: M. Harunur Rashid; Redwan Huq; Mark R. Tanner; Sandeep Chhabra; Keith K. Khoo; Rosendo Estrada; Vikas Dhawan; Satendra Chauhan; Michael W. Pennin...; Christine Beeton; Serdar Kuyucak; Raymond S. Norton
• Keywords: Docking (animal)

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