ADWX-1-A Potent Peptide Inhibitor for Kv1.3 Channel

Introduction

The voltage-gated Kv1.3 channel in effector memory T cells serves as a new therapeutic target for multiple sclerosis. The molecular weight of ADWX-1 is 4072.8 Da and the ADWX-1 peptide blocked Kv1.3 with picomolar affinity (IC50=1.89 pM), showing a 100-fold increase in activity compared with the native BmKTX toxin. The ADWX-1 also displays good selectivity on Kv1.3 over related Kv1.1 and Kv1.2 channels. In transiently transfected HEK293 cells, ADWX-1 inhibits potassium channels with IC50 values of 1.89 pM and 0.65 nM for Kv1.3 and Kv1.1, respectively.

Pharmacologic action

ADWX-1 is highly potent against the Kv1.3 channel with an IC50 of 1.89±0.53 pM, which shows a 100-fold increase in binding affinity compared to BmKTX. In addition, ADWX-1 also exhibited over 340-fold selectivity for Kv1.3 over Kv1.1 (IC50, 0.65±0.25 nM). In addition, the 100 nm ADWX-1 peptide only blocked about 10% of the peak current of the Kv1.2 channels. These data indicate that the designed ADWX-1 peptide is the most selective and potent peptide inhibitor among the identified inhibitors of Kv 1.3.

Function

In the experimental autoimmune encephalomyelitis (EAE) model in rats, ADWX-1 can reduce the clinical score and significantly reduce inflammatory infiltration. In addition, ADWX-1 reduces the levels of IL-2 and IFN-γ. In ADWX-1 treated EAE rat-derived PBMCs, IL-2 secretion is significantly reduced by stimulation with MBP. In the EAE model, ADWX-1 inhibits CD4+ CCR7-TEM cells. Moreover, ADWX-1 inhibits IL-2 secretion in CD4+ CCR7-TEM cells by NF-B and NF-AT-dependent methods.

Application prospects

The specific ADWX-1 peptide would be a viable lead in the therapy of T cell-mediated autoimmune diseases. ADWX-1 has dual inhibitory effects on channel activity and channel expression in specific CD4+CCR7-TEM cells and is a novel potent candidate therapeutic drug for Multiple sclerosis.

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S. Han, H. Yi, S. Yin, Z. Chen, H. Liu, Z. Cao, Y. Wu, and W. Li, Structural Basis of a Potent Peptide Inhibitor Designed for Kv1.3 Channel, a Therapeutic Target of Autoimmune Disease, J Biol Chem, 2008, 283, 19058-19065.