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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
Author(s) -
Chang Shih C.,
Huq Redwan,
Chhabra Sandeep,
Beeton Christine,
Pennington Michael W.,
Smith Brian J.,
Norton Raymond S.
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13294
Subject(s) - peptide , potassium channel , biology , potassium channel blocker , amino acid , effector , biochemistry , stereochemistry , chemistry , biophysics
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 + ‐channel toxin from Stichodactyla helianthus (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 50 of 34 p m 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.