N‐terminally extended analogues of the K+ channel toxin from Stichodactyla helianthus as potent and selective blockers of the voltage‐gated potassium channel Kv1.3. (23rd April 2015)

• Record Type: Journal Article
• Authors: Chang, Shih C.; Huq, Redwan; Chhabra, Sandeep; Beeton, Christine; Pennington, Michael W.; Smith, Brian J.; Norton, Raymond S.
• Is Part Of: FEBS journal. Volume 282:Number 12(2015)
• Page Start: 2247
• Page End: 2259
• Publication Date: 2015-04-23
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.13294
• Languages: English
• ISSNs: 1742-464X

Abstract

<abstract abstract-type="main" id="febs13294-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The voltage‐gated potassium channel Kv1.3 is an important target for the treatment of autoimmune diseases and asthma. Blockade of Kv1.3 by the sea anemone peptide K<sup>+</sup>‐channel toxin from <italic>Stichodactyla helianthus</italic> (ShK) inhibits the proliferation of effector memory T lymphocytes and ameliorates autoimmune diseases in animal models. However, the lack of selectivity of ShK for Kv1.3 over the Kv1.1 subtype has driven a search for Kv1.3‐selective analogues. In the present study, we describe N‐terminally extended analogues of ShK that contain a negatively‐charged Glu, designed to mimic the phosphonate adduct in earlier Kv1.3‐selective analogues, and consist entirely of common protein amino acids. Molecular dynamics simulations indicated that a Trp residue at position [‐3] of the tetrapeptide extension could form stable interactions with Pro377 of Kv1.3 and best discriminates between Kv1.3 and Kv1.1. This led to the development of ShK with an N‐terminal Glu‐Trp‐Ser‐Ser extension ([EWSS]ShK), which inhibits Kv1.3 with an IC<sub>50</sub> of 34 p<sc>m</sc> and is 158‐fold selective for Kv1.3 over Kv1.1. In addition, [EWSS]ShK is more than 2900‐fold more selective for Kv1.3 over Kv1.2 and KCa3.1 channels. As a highly Kv1.3‐selective analogue of ShK based entirely on protein amino acids, which can be produced by recombinant expression, this peptide is a valuable addition to the complement of therapeutic candidates for the treatment of autoimmune diseases.</p> </abstract>