Dataciencia

Colección SciELO Chile

Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation

Indexado

Scopus

SCOPUS_ID:105002584448

DOI

10.1016/J.JBC.2025.108387

Año

2025

Tipo

Citas Totales

Autores Afiliación Chile

Instituciones Chile

% Participación
Internacional

Autores
Afiliación Extranjera

Instituciones
Extranjeras

Abstract

Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as NaV1.5, KV1.5, and TASK-1 playing crucial roles. This study investigates acetamide-based compounds designed as multi-target inhibitors of these ion channels to address AF. Compound 6f emerged as the most potent in the series, demonstrating a strong inhibition of TASK-1 (IC50 ∼ 0.3 μM), a moderate inhibition of NaV1.5 (IC50 ∼ 21.2 μM) and a subtle inhibition of KV1.5 (IC50 ∼ 81.5 μM), alongside unexpected activation of TASK-4 (∼ 40% at 100 μM). Functional assays on human atrial cardiomyocytes from sinus rhythm (SR) and patients with AF revealed that 6f reduced action potential amplitude in SR (indicating NaV1.5 block), while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, 6f caused hyperpolarization of the resting membrane potential in AF cardiomyocytes, consistent with the observed TASK-4 activation. Mathematical modeling further validated its efficacy in reducing AF burden. Pharmacokinetic analyses suggest favorable absorption and low toxicity. These findings identify 6f as a promising multi-target therapeutic candidate for AF management.

Revista

Revista	ISSN
Journal Of Biological Chemistry	0021-9258

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Disciplinas de Investigación

WOS
Biochemistry & Molecular Biology

Scopus
Molecular Biology
Biochemistry
Cell Biology

SciELO
Sin Disciplinas

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Publicaciones WoS (Ediciones: ISSHP, ISTP, AHCI, SSCI, SCI), Scopus, SciELO Chile.

Colaboración Institucional

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Autores - Afiliación

Ord.	Autor	Género	Institución - País
1	Camargo-Ayala, Lorena	-	Universidad de Talca - Chile
2	Bedoya, Mauricio	-	Universidad Católica del Maule - Chile
3	Dasí, Albert	-	University of Oxford - Reino Unido
4	Prüser, Merten	-	Universität Heidelberg - Alemania
5	Schütte, Sven	-	Philipps-Universität Marburg - Alemania
6	Prent-Peñaloza, Luis	-	Universidad Nacional Andrés Bello - Chile
7	Adasme-Carreño, Francisco	-	Universidad Católica del Maule - Chile
8	Kiper, Aytug K.	-	Philipps-Universität Marburg - Alemania Universitätsmedizin Greifswald - Alemania
9	Rinne, Susanne	Mujer	Philipps-Universität Marburg - Alemania
10	Camargo-Ayala, Paola Andrea	-	Universidad de Talca - Chile
11	Peña-Martínez, Paula A.	-	Universidad de Talca - Chile
12	Bueno-Orovio, Alfonso	-	University of Oxford - Reino Unido
13	Varela, Diego	-	Núcleo Milenio de Enfermedades asociadas a Canales Iónicos - Chile Universidad de Chile - Chile
14	Wiedmann, Felix	-	Universität Heidelberg - Alemania
15	Márquez Montesinos, José C.E.	-	Universidad de Talca - Chile
16	Mazola, Yuliet	-	Universidad de Talca - Chile
17	Venturini, Whitney	-	Universidad Católica del Maule - Chile
18	ZUNIGA-HORMAZABAL, RAFAEL ENRIQUE	Hombre	Universidad de Talca - Chile
19	ZUNIGA-HORMAZABAL, LEANDRO ANTONIO	Hombre	Universidad de Talca - Chile
20	Schmidt, Constanze	-	Universität Heidelberg - Alemania
21	Rodriguez, Blanca	-	University of Oxford - Reino Unido
22	Ravens, Ursula	-	German Atrial Fibrillation Competence NETwork (AFNET) - Alemania Universitäts Herzzentrum Freiburg Bad Krozingen - Alemania
23	Decher, Niels	Hombre	Philipps-Universität Marburg - Alemania
24	GUTIERREZ-GARCIA, MARIA GLORIA	Mujer	Universidad de Talca - Chile
25	González, Wendy	-	Núcleo Milenio de Enfermedades asociadas a Canales Iónicos - Chile Universidad de Talca - Chile

Muestra la afiliación y género (detectado) para los co-autores de la publicación.

Financiamiento

Fuente
Fondo Nacional de Desarrollo Científico y Tecnológico
Universidad de Talca
Deutsche Forschungsgemeinschaft
Wellcome Trust
Engineering and Physical Sciences Research Council
Else Kroner-Fresenius-Stiftung
German Foundation of Heart Research
Deutsches Zentrum für Herz-Kreislaufforschung
Fondecyt-ANID
Deutsche Herzstiftung
CBSM
Basic Biomedical Sciences
Center for Bioinformatics, Simulation and Modelling
Philipps University

Muestra la fuente de financiamiento declarada en la publicación.

Agradecimientos

Agradecimiento
During the preparation of this work, the author(s) used ChatGPT (OpenAI, 2022) in order to proofread and enhance the grammatical accuracy of the manuscript. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication. W. G. conceptualization; L. C-A. M. B. A. D. M. P. S. S. Y. M. W. V. R. Z. L. Z. C. S. B. R. U. R. N. D. M. G. and W. G. data curation; L. C-A. M. B. A. D. M. P. L. P-P. F. A-C. A. K. K. S. R. P. A. C-A. P. A. P-M. A. B.-O. D. V. F. W. and J. C. E. M-M. formal analysis; M. G. W. G. L. C-A. M. B. P. P-M. P. A. C-A. L. Z. C. S. and F. W. funding acquisition; L. C-A. M. B. A. D. M. P. L. P-P. F. A-C. P. A. C-A. F. W. and J. C. E. M-M. investigation; L. C-A. M. B. A. D. M. P. F. A-C. A. K. K. S. R. P. A. C-A. F. W. S. S. Y. M. W. V. R. Z. L. Z. C. S. B. R. N. D. M. G. and W. G. methodology; W. G. project administration; L. Z. C. S. B. R. N. D. M. G. and W. G. resources; M. B. F. A-C. A. D. A. B-O. and B. R. software; R. Z. L. Z. C. S. B. R. U. R. N. D. M. G. and W. G. supervision; L. C-A. M. B. A. D. M. P. L. P-P. F. A-C. A. K. K. S. R. P. A. C-A. P. A. P-M. A. B-O. D. V. F. W. J. C. E. M-M. S. S. Y. M. W. V. R. Z. L. Z. C. S. B. R. U. R. N. D. M. G. and W. G. validation; L. C-A. M. B. A. D. M. P. A. K. K. P. A. C-A. P. A. P-M. F. W. and J. C. E. M-M. visualization; L. C-A. M. B. A. D. M. P. and F. W. writing\u2013original draft; L. C-A. M. B. A. D. M. P. L. P-P. A. K. K. S. R. D. V. C. S. B. R. U. R. N. D. M. G. and W. G writing\u2013review & editing. The authors acknowledge the Research Group of the Laboratory of Organic Synthesis and Biological Activity, Laboratory of Electrophysiology of the Institute of Physiology and Pathophysiology, Philipps University. Marburg, Germany and the Center for Bioinformatics, Simulation and Modelling (CBSM) of the University of Talca, Fondecyt Projects 1200531, 1230446 and 1230996 and FIC-R Gore Maule project 40.027.577-0. L. C-A. acknowledges the ANID National Doctorate Scholarship 2019 Folio N\u00B0 21190020. M. B. acknowledges FONDECYT-ANID for his postdoctoral grant N\u00B0 3210774. P. P-M. acknowledges the ANID National Doctorate Scholarship 2019 Folio N\u00B0 21190245. PA. C-A. acknowledges the ANID National Doctorate Scholarship 2021 Folio N\u00B0 21220448. CS was funded in part by research grants from the German Heart Foundation/German Foundation of Heart Research (F/03/19, Atrial fibrillation grant), the Else-Kr\u00F6ner Fresenius Foundation (EKFS Clinician-Scientist professorship), the German Centre for Cardiovascular Research (DZHK TRP grant, innovation cluster grant, shared expertise). C. S. ad F. W. are members of the CRC1425 and CRC1550, funded by the German Research Foundation (#422681845 and #464424253). B. R. acknowledges funding from the EPSRC Impact Acceleration Account (UKRI Grant Reference - EP/X525777/1) and Wellcome Trust Senior Fellowship in Basic Biomedical Sciences (214290/Z/18/Z). W. V. acknowledges Fondecyt-ANID Iniciacion 11251459.
The authors acknowledge the Research Group of the Laboratory of Organic Synthesis and Biological Activity, Laboratory of Electrophysiology of the Institute of Physiology and Pathophysiology, Philipps University. Marburg, Germany and the Center for Bioinformatics, Simulation and Modelling (CBSM) of the University of Talca, Fondecyt Projects 1200531, 1230446 and 1230996 and FIC-R Gore Maule project 40.027.577-0. L.C-A. acknowledges the ANID National Doctorate Scholarship 2019 Folio N\u00B0 21190020. M.B. acknowledges FONDECYT-ANID for his postdoctoral grant N\u00BA 3210774. P.P-M. acknowledges the ANID National Doctorate Scholarship 2019 Folio N\u00B0 21190245. PA.C-A. acknowledges the ANID National Doctorate Scholarship 2021 Folio N\u00B0 21220448. CS was funded in part by research grants from the German Heart Foundation /German Foundation of Heart Research (F/03/19, Atrial fibrillation grant), the Else-Kr\u00F6ner Fresenius Foundation (EKFS Clinician-Scientist professorship), the German Centre for Cardiovascular Research (DZHK TRP grant, innovation cluster grant, shared expertise). CS ad FW are members of the CRC1425 and CRC1550, funded by the German Research Foundation (#422681845 and #464424253).

Agradecimiento

During the preparation of this work, the author(s) used ChatGPT (OpenAI, 2022) in order to proofread and enhance the grammatical accuracy of the manuscript. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication. W. G. conceptualization; L. C-A. M. B. A. D. M. P. S. S. Y. M. W. V. R. Z. L. Z. C. S. B. R. U. R. N. D. M. G. and W. G. data curation; L. C-A. M. B. A. D. M. P. L. P-P. F. A-C. A. K. K. S. R. P. A. C-A. P. A. P-M. A. B.-O. D. V. F. W. and J. C. E. M-M. formal analysis; M. G. W. G. L. C-A. M. B. P. P-M. P. A. C-A. L. Z. C. S. and F. W. funding acquisition; L. C-A. M. B. A. D. M. P. L. P-P. F. A-C. P. A. C-A. F. W. and J. C. E. M-M. investigation; L. C-A. M. B. A. D. M. P. F. A-C. A. K. K. S. R. P. A. C-A. F. W. S. S. Y. M. W. V. R. Z. L. Z. C. S. B. R. N. D. M. G. and W. G. methodology; W. G. project administration; L. Z. C. S. B. R. N. D. M. G. and W. G. resources; M. B. F. A-C. A. D. A. B-O. and B. R. software; R. Z. L. Z. C. S. B. R. U. R. N. D. M. G. and W. G. supervision; L. C-A. M. B. A. D. M. P. L. P-P. F. A-C. A. K. K. S. R. P. A. C-A. P. A. P-M. A. B-O. D. V. F. W. J. C. E. M-M. S. S. Y. M. W. V. R. Z. L. Z. C. S. B. R. U. R. N. D. M. G. and W. G. validation; L. C-A. M. B. A. D. M. P. A. K. K. P. A. C-A. P. A. P-M. F. W. and J. C. E. M-M. visualization; L. C-A. M. B. A. D. M. P. and F. W. writing\u2013original draft; L. C-A. M. B. A. D. M. P. L. P-P. A. K. K. S. R. D. V. C. S. B. R. U. R. N. D. M. G. and W. G writing\u2013review & editing. The authors acknowledge the Research Group of the Laboratory of Organic Synthesis and Biological Activity, Laboratory of Electrophysiology of the Institute of Physiology and Pathophysiology, Philipps University. Marburg, Germany and the Center for Bioinformatics, Simulation and Modelling (CBSM) of the University of Talca, Fondecyt Projects 1200531, 1230446 and 1230996 and FIC-R Gore Maule project 40.027.577-0. L. C-A. acknowledges the ANID National Doctorate Scholarship 2019 Folio N\u00B0 21190020. M. B. acknowledges FONDECYT-ANID for his postdoctoral grant N\u00B0 3210774. P. P-M. acknowledges the ANID National Doctorate Scholarship 2019 Folio N\u00B0 21190245. PA. C-A. acknowledges the ANID National Doctorate Scholarship 2021 Folio N\u00B0 21220448. CS was funded in part by research grants from the German Heart Foundation/German Foundation of Heart Research (F/03/19, Atrial fibrillation grant), the Else-Kr\u00F6ner Fresenius Foundation (EKFS Clinician-Scientist professorship), the German Centre for Cardiovascular Research (DZHK TRP grant, innovation cluster grant, shared expertise). C. S. ad F. W. are members of the CRC1425 and CRC1550, funded by the German Research Foundation (#422681845 and #464424253). B. R. acknowledges funding from the EPSRC Impact Acceleration Account (UKRI Grant Reference - EP/X525777/1) and Wellcome Trust Senior Fellowship in Basic Biomedical Sciences (214290/Z/18/Z). W. V. acknowledges Fondecyt-ANID Iniciacion 11251459.

The authors acknowledge the Research Group of the Laboratory of Organic Synthesis and Biological Activity, Laboratory of Electrophysiology of the Institute of Physiology and Pathophysiology, Philipps University. Marburg, Germany and the Center for Bioinformatics, Simulation and Modelling (CBSM) of the University of Talca, Fondecyt Projects 1200531, 1230446 and 1230996 and FIC-R Gore Maule project 40.027.577-0. L.C-A. acknowledges the ANID National Doctorate Scholarship 2019 Folio N\u00B0 21190020. M.B. acknowledges FONDECYT-ANID for his postdoctoral grant N\u00BA 3210774. P.P-M. acknowledges the ANID National Doctorate Scholarship 2019 Folio N\u00B0 21190245. PA.C-A. acknowledges the ANID National Doctorate Scholarship 2021 Folio N\u00B0 21220448. CS was funded in part by research grants from the German Heart Foundation /German Foundation of Heart Research (F/03/19, Atrial fibrillation grant), the Else-Kr\u00F6ner Fresenius Foundation (EKFS Clinician-Scientist professorship), the German Centre for Cardiovascular Research (DZHK TRP grant, innovation cluster grant, shared expertise). CS ad FW are members of the CRC1425 and CRC1550, funded by the German Research Foundation (#422681845 and #464424253).