Peptide blockers of Kv1. 3 channels in T cells as therapeutics for autoimmune disease

KG Chandy, RS Norton - Current opinion in chemical biology, 2017 - Elsevier
Current opinion in chemical biology, 2017Elsevier
Highlights•The K v 1.3 channel in T cells is a validated therapeutic target for autoimmune
diseases.•The most potent blockers are peptides from scorpions and sea anemones.•Phase
1 clinical trials with dalazatide (ShK-186) show highly promising results.•Buccal and
pulmonary administration are suitable for delivering Kv1. 3-blocking peptides.•Peptides can
be conjugated with larger carriers but this may not be necessary for efficacy in vivo.The
voltage-gated K v 1.3 channel in T lymphocytes is a validated therapeutic target for diverse …
Highlights
  • The K v 1.3 channel in T cells is a validated therapeutic target for autoimmune diseases.
  • The most potent blockers are peptides from scorpions and sea anemones.
  • Phase 1 clinical trials with dalazatide (ShK-186) show highly promising results.
  • Buccal and pulmonary administration are suitable for delivering Kv1. 3-blocking peptides.
  • Peptides can be conjugated with larger carriers but this may not be necessary for efficacy in vivo.
The voltage-gated K v 1.3 channel in T lymphocytes is a validated therapeutic target for diverse autoimmune diseases. Here we review the discovery of K v 1.3, its physiological role in T cells, and why it is an attractive target for modulating autoimmune responses. We focus on peptide inhibitors because the first K v 1.3-selective inhibitor in human trials is a peptide derived from a marine organism. Two broad classes of peptides block K v 1.3, the first from scorpions and the second from sea anemones. We describe their structures, their binding site in the external vestibule of K v 1.3, how they have been engineered to improve K v 1.3-specificity, and their pharmacokinetic and pharmacodynamic properties. Finally, we highlight the therapeutic potential of K v 1.3 peptide inhibitors to treat autoimmune diseases without compromising protective immune responses.
Elsevier