Study of kv4.3 channelosome: novel kchip2 ligands as pharmacological tools
| Autor: | Martinez-Salas, P., Viedma-Barba, C., Benito-Bueno, Ángela de, Socuéllamos, Paula G., Daniel-Mozo, M., Albert, Armando, Martín-Martínez, Mercedes, Valenzuela, Carmen, Gutiérrez-Rodríguez, Marta |
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| Přispěvatelé: | Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España) |
| Rok vydání: | 2022 |
| Předmět: | |
| Popis: | Trabajo presentado en el VIII Symposia of medicinal chemistry young researchers, celebrado en Barcelona (España) el 22 de julio de 2022. Ion channels are macromolecular complexes present in the plasma membrane and in intracellular organelles of the cells, where they play important functions. The dysfunction of these channels results in several disorders named channelopathies, which represent a challenge for study and treatment.[1] We are focused on voltage-gated potassium channels, specifically on KV4.3. Within the heart, KV4.3 channels generate the transient outward potassium current (ITO). However, ITO characteristics are only observed when KV4.3 assembles with accessory subunits as KChIP2 and DPP6. KV4.3 channelosome play a key role in atrial fibrillation (AF), the most common cardiac arrhythmia, with an estimated prevalence in the general population of 1.5–2%. However, current antiarrhythmic drugs for AF prevention have limited efficacy and considerable potential for adverse effects.[2] KChIP2 (Potassium Channel Interacting Protein 2) belongs to the calcium binding protein superfamily. It is the KChIP member predominantly expressed in heart and a key regulator of cardiac action potential duration. Novel KChIP2 ligands could be a useful pharmacological tool to understand the role of KV4.3 channelosome in AF and it could help to discover new treatments for AF. [3] In this communication, we will describe a multidisciplinary approach that, starting with a structure-based virtual screening, followed by an iterative process of synthesis/biological evaluation/docking studies, has led to the identification of new KChIP2 ligands. PID2019-104366RB-C21, PID2019-104366RB-C22, PID2020-114256RB-I00 and PID2020-119805RB-I00 grants funded by MCIN/AEI/10.13039/501100011033; and PIE202180E073 and 2019AEP148 funded by CSIC. C.V.B. holds PRE2020-093542 FPI grant funded by MCIN/AEI/10.13039/501100011033. PGS was recipient of an FPU grant (FPU17/02731). AB-B holds BES-2017-080184 FPI grant and A.P-L.holds RYC2018-023837-I grant both funded by MCIN/AEI/ 10.13039/501100011033 and by “ESF Investing in your future”. |
| Databáze: | OpenAIRE |
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