The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases.

Abstract

The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K⁺ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the "evolutionary" Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel-specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies.

• Authors: Fang Ye, Youtian Hu, Weiwei Yu, Zili Xie, Jun Hu, Zhijian Cao, Wenxin Li, Yingliang Wu
• Journal: Toxins (Toxins (Basel)) Vol. 8 Issue 4 Pg. 115 (Apr 19 2016) ISSN: 2072-6651 [Electronic] Switzerland
• PMID: 27104568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD3 Complex
• Cytokines
• Immunologic Factors
• KTX toxin, Buthus
• Kv1.3 Potassium Channel
• Potassium Channel Blockers
• Scorpion Venoms
• Ovalbumin

Topics

• Amino Acid Sequence
• Animals
• Autoimmune Diseases
• CD3 Complex
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cytokines (metabolism)
• Female
• HEK293 Cells
• Humans
• Hypersensitivity, Delayed (chemically induced, drug therapy)
• Immunologic Factors (chemistry, pharmacology, therapeutic use)
• Jurkat Cells
• Kv1.3 Potassium Channel (physiology)
• Ovalbumin
• Potassium Channel Blockers (chemistry, pharmacology, therapeutic use)
• Rats, Inbred Lew
• Scorpion Venoms (chemistry, pharmacology, therapeutic use)
• Scorpions
• Sequence Alignment
• T-Lymphocytes (drug effects, metabolism)