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

2018-11-16

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.

References:

K. G. Chandy, H. Wulff, C. Beeton, M. Pennington, G. A. Gutman, and M. D. Cahalan, K+ channels as targets for specific immunomodulation, Trends Pharmacol. Sci. 2004, 25, 280–289.

Z. Li, W. Liu, S. Han, B. Peng, J. Yin, Y. Wu, X. He, and W. Li, Selective inhibition of CCR72 effector memory T cell activation by a novel peptide targeting Kv1.3 channel in a rat experimental autoimmune encephalomyelitis model. J Biol Chem 2012, 287, 29479–29494.

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.

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