A designer ligand specific for Kv1.3 channels from a scorpion neurotoxin-based library

@article{Takcs2009ADL,
  title={A designer ligand specific for Kv1.3 channels from a scorpion neurotoxin-based library},
  author={Zolt{\'a}n de Tak{\'a}cs and Megan Toups and Astrid Kollewe and Erik C. Johnson and Luis G. Cuello and Gr{\'e}gory Driessens and Matthew Biancalana and Akiko Koide and Cristiano G Ponte and Eduardo Perozo and Thomas F. Gajewski and Guilherme Suarez-Kurtz and Shohei Koide and Steve A.N. Goldstein},
  journal={Proceedings of the National Academy of Sciences},
  year={2009},
  volume={106},
  pages={22211 - 22216}
}
Venomous animals immobilize prey using protein toxins that act on ion channels and other targets of biological importance. Broad use of toxins for biomedical research, diagnosis, and therapy has been limited by inadequate target discrimination, for example, among ion channel subtypes. Here, a synthetic toxin is produced by a new strategy to be specific for human Kv1.3 channels, critical regulators of immune T cells. A phage display library of 11,200 de novo proteins is designed using the α-KTx… Expand
ImKTx88, a novel selective Kv1.3 channel blocker derived from the scorpion Isometrus maculates.
TLDR
Electrophysiological experiments indicated that the rImKTx88 peptide had a novel pharmacological profile: it inhibited Kv1.3 channel current with an IC₅₀ of 91 ± 42 pM, and exhibited very good selectivity for Kv2.1 (4200-fold) and K v1.2 (93000-fold), suggesting that it may serve as a potential drug candidate in the therapy of autoimmune diseases. Expand
Designer and natural peptide toxin blockers of the KcsA potassium channel identified by phage display
TLDR
In isolation of toxins for one such orphan target, KcsA, a potassium channel that has been fundamental to delineating the structural basis for ion channel function, the 3D structure and action of Hui1 validate the strategy and reveal an unexpected basis for channel inhibition. Expand
Margatoxin is a non-selective inhibitor of human Kv 1 . 3 K + channels 2 3
Abstract: During the last few decades many short-chain peptides have been isolated from the venom of different scorpion species. These toxins inhibit a variety of K+ channels by binding to andExpand
Scorpion Toxins Specific for Potassium (K+) Channels: A Historical Overview of Peptide Bioengineering
TLDR
Bioengineered scorpion toxins have been monumental to the evolution of channel science, and are now serving as templates for the development of invaluable experimental molecular therapeutics. Expand
The Kv1.3 K+ channel in the immune system and its "precision pharmacology" using peptide toxins.
TLDR
Despite the significant progress in the field of Kv1.3 molecular pharmacology several progressive questions remain to be elucidated and discussed here, including the conjugation of the peptides to carriers to increase the residency time of the proteins in the circulation and the use of rational drug design to create novel peptide inhibitors. Expand
Tuning Scorpion Toxin Selectivity: Switching From KV1.1 to KV1.3
TLDR
MeKTx13-3 and its derivatives are attractive tools to study the structure-function relationship in potassium channel blockers and are converted into a new specific KV1.3 affinity as measured using the voltage-clamp technique on mammalian channels expressed in Xenopus oocytes. Expand
Identification of a new specific Kv1.3 channel blocker, Ctri9577, from the scorpion Chaerilus tricostatus
TLDR
The sequence analysis showed that the mature peptide of Ctri9577 contained 39 amino acid residues including six conserved cysteines, whose low sequence similarity indicated that it was a new member of α-KTx15 subfamily, and present a novel potential drug candidate targeting Kv1.3 channel. Expand
Molecular Diversity and Functional Evolution of Scorpion Potassium Channel Toxins*
TLDR
Molecular characterization of seven new KTxs in the scorpion Mesobuthus eupeus by cDNA cloning combined with biochemical approaches shows that all these KTxs share a conserved cysteine-stabilized α-helix/β-sheet structural motif despite the differences in protein sequence and size. Expand
Hg1, Novel Peptide Inhibitor Specific for Kv1.3 Channels from First Scorpion Kunitz-type Potassium Channel Toxin Family*
TLDR
The first scorpion Kunitz-type potassium channel toxin family with three groups and seven members is identified, of which a novel inhibitor, Hg1, is specific for Kv1.3 channel, and their structural and functional diversity strongly suggest that Kunitzer-type toxins are a new source to screen and design potential peptides for diagnosing and treating Kv 1.3-mediated autoimmune diseases. Expand
Endogenous animal toxin-like human β-defensin 2 inhibits own K+ channels through interaction with channel extracellular pore region
TLDR
HBD2 is evidenced as the first characterized endogenous peptide inhibitor of human potassium channels, but also paved a promising avenue to investigate newly discovered function of hBD2 as Kv1.3 channel inhibitor in the immune system and other fields. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 53 REFERENCES
Engineering-specific pharmacological binding sites for peptidyl inhibitors of potassium channels into KcsA.
TLDR
The results demonstrate that the pharmacological profile of peptide toxins can be incorporated into KcsA-Kv1.X channels, and may facilitate the high-throughput screening of ligand libraries aimed at the discovery of novel potassium channel modulators. Expand
Structural Basis of a Potent Peptide Inhibitor Designed for Kv1.3 Channel, a Therapeutic Target of Autoimmune Disease*
TLDR
The design of a new peptide inhibitor that is potent and selective for Kv1.3, and the successful design of ADWX-1 suggests that rational design based on the structural model of the peptide-channel complex should accelerate the development of diagnostic and therapeutic agents for human channelopathies. Expand
Current views on scorpion toxins specific for K+-channels.
TLDR
The evolutionary tree indicates that several clusters of divergent peptides show preference for specific subtypes of channels, and four different interacting modes were identified to exist between scorpion toxins and the various sub types of K+-channels. Expand
The charybdotoxin family of K+ channel-blocking peptides
TLDR
The molecular characteristics of these peptides, which have been named either whimsically or according to the scorpion species in which the peptide is found, and the unique kinds of molecular information they have provided about the K+ channels that act as their receptors are summarized. Expand
Generating a High Affinity Scorpion Toxin Receptor in KcsA-Kv1.3 Chimeric Potassium Channels*
TLDR
A structural model for the complex between KcsA-Kv1.3 chimeras and kaliotoxin is developed to aid future pharmacological studies of K+ channels and shows that a subregion of the S5-S6 linker may be an important determinant of the pharmacological profile of K- channels. Expand
Engineering a Stable and Selective Peptide Blocker of the Kv1.3 Channel in T Lymphocytes
TLDR
Kv1.3 potassium channels maintain the membrane potential of effector memory (TEM) T cells that are important mediators of multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis and ShK-192 has potential as a therapeutic for autoimmune diseases mediated by TEM cells. Expand
Novel alpha-KTx peptides from the venom of the scorpion Centruroides elegans selectively blockade Kv1.3 over IKCa1 K+ channels of T cells.
TLDR
The electrophysiological assay (whole-cell patch-clamp) showed that out of the five peptides, Ce1, Ce2 and Ce4 were effective blockers of Kv1.3 channels of human T lymphocytes, whereas these peptides did not inhibit the Ca2+-activated K+ channels of the same cells. Expand
KTX3, the kaliotoxin from Buthus occitanus tunetanus scorpion venom: one of an extensive family of peptidyl ligands of potassium channels.
A new ligand of the K+ channels sensitive to KTX was purified from the venom of Buthus occitanus tunetanus, using two steps of high-performance-liquid-chromatography and by following its ability toExpand
A new Kaliotoxin selective towards Kv1.3 and Kv1.2 but not Kv1.1 channels expressed in oocytes.
TLDR
The purification, the sequencing, and the immunological and biological characterization of a new Kaliotoxin analog, Aam-KTX, from the venom of the scorpion Androctonus amoreuxi brought putative answers to this difference in selectivity. Expand
Purification and characterization of three inhibitors of voltage-dependent K+ channels from Leiurus quinquestriatus var. hebraeus venom.
Three new toxins from the venom of the scorpion Leiurus quinquestriatus var. hebraeus have been identified on the basis of their ability to block the Shaker K+ channel. These toxins have beenExpand
...
1
2
3
4
5
...