New approaches for the identification of KChIP2 ligands to study the KV4.3 channelosome in atrial fibrillati

Resumen del trabajo presentado en el VIII Congreso Red Española de Canales iónico, celebrado en Alicante (España) del 24 al 27 de mayo 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. Kv4.3 is expressed in smooth muscle, heart and brain. Within the heart, Kv4.3 channels generate the transient outward potassium current (ITO). However, ITO characteristics are only observed when Kv4.3 assemble 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. The identification of novel KChIP2 ligands could be useful to understand the role of KV4.3 channelosome in AF and it could help to discover new treatments for AF. [3] In this regard, structure-based virtual screening could be an important tool to accelerate the identification of novel KChIP2 ligands. In this communication, we will describe a multidisciplinary approach that, starting with a structurebased 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

New approaches for the identification of KChIP2 ligands to study the KV4.3 channelosome in atrial fibrillati

Resumen del trabajo presentado en el VIII Congreso Red Española de Canales iónico, celebrado en Alicante (España) del 24 al 27 de mayo 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. Kv4.3 is expressed in smooth muscle, heart and brain. Within the heart, Kv4.3 channels generate the transient outward potassium current (ITO). However, ITO characteristics are only observed when Kv4.3 assemble 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. The identification of novel KChIP2 ligands could be useful to understand the role of KV4.3 channelosome in AF and it could help to discover new treatments for AF. [3] In this regard, structure-based virtual screening could be an important tool to accelerate the identification of novel KChIP2 ligands. In this communication, we will describe a multidisciplinary approach that, starting with a structurebased 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

The Canfranc Axion Detection Experiment (CADEx): Search for axions at 90 GHz with Kinetic Inductance Detectors

We propose a novel experiment, the Canfranc Axion Detection Experiment (CADEx), to probe dark matter axions with masses in the range 330-460 $\mu$eV, within the W-band (80-110 GHz), an unexplored parameter space in the well-motivated dark matter window of Quantum ChromoDynamics (QCD) axions. The experimental design consists of a microwave resonant cavity haloscope in a high static magnetic field coupled to a highly sensitive detecting system based on Kinetic Inductance Detectors via optimized quasi-optics (horns and mirrors). The experiment is in preparation and will be installed in the dilution refrigerator of the Canfranc Underground Laboratory. Sensitivity forecasts for axion detection with CADEx, together with the potential of the experiment to search for dark photons, are presented.Comment: 23 pages, 10 figure