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 > 2 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.
authors.affiliation: 1] Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia [2] School of Physics, University of Sydney, New South Wales 2006, Australia.
authors.forename: M Harunur
authors.initials: MH
authors.lastname: Rashid
authors.affiliation: 1] Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA [2] Graduate Program in Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Redwan
authors.initials: R
authors.lastname: Huq
authors.affiliation: 1] Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA [2] Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Tanner
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Chhabra
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Keith K
authors.initials: KK
authors.lastname: Khoo
authors.affiliation: Peptides International, 11621 Electron Drive, Louisville, KY 40299, USA.
authors.forename: Rosendo
authors.initials: R
authors.lastname: Estrada
authors.affiliation: Peptides International, 11621 Electron Drive, Louisville, KY 40299, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Dhawan
authors.affiliation: Peptides International, 11621 Electron Drive, Louisville, KY 40299, USA.
authors.forename: Satendra
authors.initials: S
authors.lastname: Chauhan
authors.affiliation: Peptides International, 11621 Electron Drive, Louisville, KY 40299, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
authors.affiliation: School of Physics, University of Sydney, New South Wales 2006, Australia.
authors.forename: Serdar
authors.initials: S
authors.lastname: Kuyucak
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D020128:Inhibitory Concentration 50; D051662:Kv1.1 Potassium Channel / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D012604:Scorpion Venoms / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D051664:Kv1.3 Potassium Channel; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; C109471:TX1 toxin, Heterometrus spinnifer; D051662:Kv1.1 Potassium Channel