ArticleMolecular pharmacology2009
Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 134 citations in OpenAlex.
- Recent advances in the pharmacology of voltage-gated ion channels.Pharmacological reviews · 2025Review
- Article
- Activity of Potassium Channel BmK-NSPK Inhibitor Regulated by Basic Amino Acid Residues: Novel Insight into the Diverse Peptide Pharmacology.Molecules (Basel, Switzerland) · 2025Article
- Voltage-Gated KMarine drugs · 2024Review
- Structure of the voltage-gated potassium channel KChannels (Austin, Tex.) · 2023Review
- Article
- Genomic, functional and structural analyses elucidate evolutionary innovation within the sea anemone 8 toxin family.BMC biology · 2023Article
- Characterisation of Elevenin-Vc1 from the Venom ofMarine drugs · 2023Article
- A ShK-like Domain fromToxins · 2022Article
- Molecular and Functional Characterization of a Novel Kunitz-Type Toxin-like Peptide in the Giant Triton SnailMarine drugs · 2022Article
- Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators.Nature communications · 2022Article
- Atto488-Agitoxin 2-A Fluorescent Ligand with Increased Selectivity for Kv1.3 Channel Binding Site.Bioengineering (Basel, Switzerland) · 2022Article
- Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The toxin mimic FS48 from the salivary gland of Xenopsylla cheopis functions as a Kv1.3 channel-blocking immunomodulator of T cell activation.The Journal of biological chemistry · 2022Article
- Pharmacological Approaches to Studying Potassium Channels.Handbook of experimental pharmacology · 2021Review
- Immunological Responses to Envenomation.Frontiers in immunology · 2021Review
- Altered CaInternational journal of molecular sciences · 2020Review
- Proteomic Analysis of the Venom of JellyfishesMarine drugs · 2020Article
- Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds.Marine drugs · 2020Review
- From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery.Frontiers in pharmacology · 2020Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 4 institutions in 3 countries.
Funding
Abstract
Kv1.3 potassium channels maintain the membrane potential of effector memory (T(EM)) T cells that are important mediators of multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. The polypeptide ShK-170 (ShK-L5), containing an N-terminal phosphotyrosine extension of the Stichodactyla helianthus ShK toxin, is a potent and selective blocker of these channels. However, a stability study of ShK-170 showed minor pH-related hydrolysis and oxidation byproducts that were exacerbated by increasing temperatures. We therefore engineered a series of analogs to minimize the formation of these byproducts. The analog with the greatest stability, ShK-192, contains a nonhydrolyzable phosphotyrosine surrogate, a methionine isostere, and a C-terminal amide. ShK-192 shows the same overall fold as ShK, and there is no evidence of any interaction between the N-terminal adduct and the rest of the peptide. The docking configuration of ShK-192 in Kv1.3 shows the N-terminal para-phosphonophenylalanine group lying at the junction of two channel monomers to form a salt bridge with Lys(411) of the channel. ShK-192 blocks Kv1.3 with an IC(50) of 140 pM and exhibits greater than 100-fold selectivity over closely related channels. After a single subcutaneous injection of 100 microg/kg, approximately 100 to 200 pM concentrations of active peptide is detectable in the blood of Lewis rats 24, 48, and 72 h after the injection. ShK-192 effectively inhibits the proliferation of T(EM) cells and suppresses delayed type hypersensitivity when administered at 10 or 100 microg/kg by subcutaneous injection once daily. ShK-192 has potential as a therapeutic for autoimmune diseases mediated by T(EM) cells.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.