Of Seven New K+ Channel Inhibitor Peptides of Centruroides bonito, α-KTx 2.24 Has a Picomolar Affinity for Kv1.2

Kashmala Shakeel; Timoteo Olamendi-Portugal; Muhammad Umair Naseem; Baltazar Becerril; Fernando Z Zamudio; Gustavo Delgado-Prudencio; Lourival Domingos Possani; Gyorgy Panyi

doi:10.3390/toxins15080506

Of Seven New K⁺ Channel Inhibitor Peptides of Centruroides bonito, α-KTx 2.24 Has a Picomolar Affinity for Kv1.2

Toxins (Basel). 2023 Aug 15;15(8):506. doi: 10.3390/toxins15080506.

Authors

Kashmala Shakeel¹, Timoteo Olamendi-Portugal², Muhammad Umair Naseem¹, Baltazar Becerril², Fernando Z Zamudio², Gustavo Delgado-Prudencio², Lourival Domingos Possani², Gyorgy Panyi¹

Affiliations

¹ Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Egyetem ter. 1, 4032 Debrecen, Hungary.
² Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Av. Universidad 2001, Cuernavaca 62210, Mexico.

Abstract

Seven new peptides denominated CboK1 to CboK7 were isolated from the venom of the Mexican scorpion Centruroides bonito and their primary structures were determined. The molecular weights ranged between 3760.4 Da and 4357.9 Da, containing 32 to 39 amino acid residues with three putative disulfide bridges. The comparison of amino acid sequences with known potassium scorpion toxins (KTx) and phylogenetic analysis revealed that CboK1 (α-KTx 10.5) and CboK2 (α-KTx 10.6) belong to the α-KTx 10.x subfamily, whereas CboK3 (α-KTx 2.22), CboK4 (α-KTx 2.23), CboK6 (α-KTx 2.21), and CboK7 (α-KTx 2.24) bear > 95% amino acid similarity with members of the α-KTx 2.x subfamily, and CboK5 is identical to Ce3 toxin (α-KTx 2.10). Electrophysiological assays demonstrated that except CboK1, all six other peptides blocked the Kv1.2 channel with Kd values in the picomolar range (24-763 pM) and inhibited the Kv1.3 channel with comparatively less potency (Kd values between 20-171 nM). CboK3 and CboK4 inhibited less than 10% and CboK7 inhibited about 42% of Kv1.1 currents at 100 nM concentration. Among all, CboK7 showed out-standing affinity for Kv1.2 (Kd = 24 pM), as well as high selectivity over Kv1.3 (850-fold) and Kv1.1 (~6000-fold). These characteristics of CboK7 may provide a framework for developing tools to treat Kv1.2-related channelopathies.

Keywords: CboK; Centruroides bonito; Kv1.2; Kv1.2 channelopathies; Kv1.3; electrophysiology; scorpion toxin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids
Animals
Peptides / pharmacology
Perciformes*
Phylogeny
Scorpions*

Substances

Peptides
Amino Acids

Supplementary concepts

Centruroides

Grants and funding

The following grants supported the work: Research grants from Hungarian National Research, Development, and Innovation Office (K143071 to G.P. and M.U.N.) and partially financed by CONACYT (National Conseil of Science and Technology) of Mexico PRONACE number 303045 and DGAPA Dirección General del Personal Académico (IN200323) (to L.D.P). This work was supported by the Richter Gedeon Talentum Foundation (to K.S.).