Identification of a new selective ligand for targeting neuronal KV4.3/KChIP3 over cardiac KV4.3/KChIP2 channels
The present study aimed to discover novel KChIP ligands as pharmacological tools for modulating the KV4.3/KChIP channels. A multidisciplinary approach, combining medicinal chemistry and electrophysiology studies, led to the successfully identification of a novel KV4.3/KChIP modulator (IQM-22110). It...
| Autores: | , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2026 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:dnet:digitalcsic_::1281a39a5d88d10565607ae4feecdf4f |
| Acceso en línea: | http://hdl.handle.net/10261/428819 https://api.elsevier.com/content/abstract/scopus_id/105033646579 |
| Access Level: | acceso abierto |
| Palabra clave: | Cardiac potassium channels currents K(V)4.3/KChIP3 channel modulators K(V)4channelopathies KChIP3 ligands |
| Sumario: | The present study aimed to discover novel KChIP ligands as pharmacological tools for modulating the KV4.3/KChIP channels. A multidisciplinary approach, combining medicinal chemistry and electrophysiology studies, led to the successfully identification of a novel KV4.3/KChIP modulator (IQM-22110). Its design was guided by the previous knowledge of the (phenylacetamido)benzoic acid moiety as suitable scaffold, along with virtual screening of a focused chemical library that suggested improved KChIP3 binding upon incorporation of an additional aromatic ring. IQM-22110 was selected for synthesis and identified as a potent KChIP3 ligand. Its electrophysiological effects on KV4.3/KChIP3 currents indicate that IQM-22110 binds to a high affinity site in KV4.3/KChIP3 channels that it is not present in KV4.3/KChIP2 or KV4.3. To the best of our knowledge, here we describe the first KChIP3 ligand that selectively modulates KV4.3/KChIP3 versus KV4.3/KChIP2 and KV4.3 channels at nanomolar concentration. Since KChIP2 is predominantly expressed in cardiac tissue, this selectivity may enable the development of KV4.3/KChIP3-targeted therapeutics with reduced risk of cardiac side effects. Computational and site-directed mutagenesis studies allowed the identification of IQM-22110's binding site on KChIP3. Knowledge gained from structural and functional studies with this novel KChIP3 ligand could establish the basis for drug discovery programs fostering treatments for diseases in which KV4.3/KChIPs channels are involved. |
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