Publicaciones de Yuliet Reyes Mazola
2025
Camargo-Ayala, Lorena; Bedoya, Mauricio; Dasí, Albert; Pruser, Merten; Schutte, Sven; Prent-Peñaloza, Luis; Adasme-Carreño, Francisco; Kiper, Aytug K; Rinné, Susanne; Camargo-Ayala, Paola Andrea; Peña-Martínez, Paula Andrea; Bueno-Orovio, Alfonso; Varela, Diego; Wiedmann, Felix; Montesinos, José Carlos Estanislao Márquez; Mazola, Yuliet; Venturini, Whitney; Zúñiga, Rafael; Zúñiga, Leandro; Schmidt, Constanze; Rodriguez, Blanca; Ravens, Ursula; Decher, Niels; Gutierrez, Margarita; González, Wendy
2025.
@bachelorthesis{Camargo-Ayala2025,
title = {Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation},
author = {Lorena Camargo-Ayala and Mauricio Bedoya and Albert Dasí and Merten Pruser and Sven Schutte and Luis Prent-Peñaloza and Francisco Adasme-Carreño and Aytug K Kiper and Susanne Rinné and Paola Andrea Camargo-Ayala and Paula Andrea Peña-Martínez and Alfonso Bueno-Orovio and Diego Varela and Felix Wiedmann and José Carlos Estanislao Márquez Montesinos and Yuliet Mazola and Whitney Venturini and Rafael Zúñiga and Leandro Zúñiga and Constanze Schmidt and Blanca Rodriguez and Ursula Ravens and Niels Decher and Margarita Gutierrez and Wendy González},
doi = {10.1016/j.jbc.2025.108387 },
year = {2025},
date = {2025-03-05},
urldate = {2025-03-05},
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.
},
keywords = {},
pubstate = {published},
tppubtype = {bachelorthesis}
}
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.
2024
Peña-Münzenmayer, Gaspar; George, Alvin T.; Llontop, Nuria; Mazola, Yuliet; Apablaza, Natalia; Spichiger, Carlos; Brauchi, Sebastián; Sarmiento, José; Zúñiga, Leandro; González, Wendy; Catalán, Marcelo A.
K+-Driven Cl−/HCO3− Exchange Mediated by Slc4a8 and Slc4a10 Artículo de revista
En: International Journal of Molecular Sciences, vol. 25, no 8, pp. 4575, 2024, ISSN: 1422-0067.
@article{pena-munzenmayer_k-driven_2024,
title = {K+-Driven Cl−/HCO3− Exchange Mediated by Slc4a8 and Slc4a10},
author = {Gaspar Peña-Münzenmayer and Alvin T. George and Nuria Llontop and Yuliet Mazola and Natalia Apablaza and Carlos Spichiger and Sebastián Brauchi and José Sarmiento and Leandro Zúñiga and Wendy González and Marcelo A. Catalán},
url = {https://www.mdpi.com/1422-0067/25/8/4575},
doi = {10.3390/ijms25084575},
issn = {1422-0067},
year = {2024},
date = {2024-04-01},
urldate = {2024-12-14},
journal = {International Journal of Molecular Sciences},
volume = {25},
number = {8},
pages = {4575},
abstract = {Slc4a genes encode various types of transporters, including Na+-HCO3− cotransporters, Cl−/HCO3− exchangers, or Na+-driven Cl−/HCO3− exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl−/HCO3− exchanger, which can be driven by either Na+ or K+, prompting investigation into whether other Slc4a members facilitate cation-dependent anion transport. In the present study, we show that either Na+ or K+ drive Cl−/HCO3− exchanger activity in cells overexpressing Slc4a8 or Slc4a10. Further characterization of cation-driven Cl−/HCO3− exchange demonstrated that Slc4a8 and Slc4a10 also mediate Cl− and HCO3−-dependent K+ transport. Full-atom molecular dynamics simulation on the recently solved structure of Slc4a8 supports the coordination of K+ at the Na+ binding site in S1. Sequence analysis shows that the critical residues coordinating monovalent cations are conserved among mouse Slc4a8 and Slc4a10 proteins. Together, our results suggest that Slc4a8 and Slc4a10 might transport K+ in the same direction as HCO3− ions in a similar fashion to that described for Na+ transport in the rat Slc4a8 structure.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Slc4a genes encode various types of transporters, including Na+-HCO3− cotransporters, Cl−/HCO3− exchangers, or Na+-driven Cl−/HCO3− exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl−/HCO3− exchanger, which can be driven by either Na+ or K+, prompting investigation into whether other Slc4a members facilitate cation-dependent anion transport. In the present study, we show that either Na+ or K+ drive Cl−/HCO3− exchanger activity in cells overexpressing Slc4a8 or Slc4a10. Further characterization of cation-driven Cl−/HCO3− exchange demonstrated that Slc4a8 and Slc4a10 also mediate Cl− and HCO3−-dependent K+ transport. Full-atom molecular dynamics simulation on the recently solved structure of Slc4a8 supports the coordination of K+ at the Na+ binding site in S1. Sequence analysis shows that the critical residues coordinating monovalent cations are conserved among mouse Slc4a8 and Slc4a10 proteins. Together, our results suggest that Slc4a8 and Slc4a10 might transport K+ in the same direction as HCO3− ions in a similar fashion to that described for Na+ transport in the rat Slc4a8 structure.
2022
Arévalo, Bárbara; Bedoya, Mauricio; Kiper, Aytug K.; Vergara, Fernando; Ramírez, David; Mazola, Yuliet; Bustos, Daniel; Zúñiga, Rafael; Cikutovic, Rocio; Cayo, Angel; Rinné, Susanne; Ramirez-Apan, M. Teresa; Sepúlveda, Francisco V.; Cerda, Oscar; López-Collazo, Eduardo; Decher, Niels; Zúñiga, Leandro; Gutierrez, Margarita; González, Wendy
Selective TASK-1 Inhibitor with a Defined Structure–Activity Relationship Reduces Cancer Cell Proliferation and Viability Artículo de revista
En: Journal of Medicinal Chemistry, vol. 65, no 22, pp. 15014–15027, 2022, ISSN: 0022-2623, 1520-4804.
@article{arevalo_selective_2022,
title = {Selective TASK-1 Inhibitor with a Defined Structure–Activity Relationship Reduces Cancer Cell Proliferation and Viability},
author = {Bárbara Arévalo and Mauricio Bedoya and Aytug K. Kiper and Fernando Vergara and David Ramírez and Yuliet Mazola and Daniel Bustos and Rafael Zúñiga and Rocio Cikutovic and Angel Cayo and Susanne Rinné and M. Teresa Ramirez-Apan and Francisco V. Sepúlveda and Oscar Cerda and Eduardo López-Collazo and Niels Decher and Leandro Zúñiga and Margarita Gutierrez and Wendy González},
url = {https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00378},
doi = {10.1021/acs.jmedchem.1c00378},
issn = {0022-2623, 1520-4804},
year = {2022},
date = {2022-11-01},
urldate = {2024-12-14},
journal = {Journal of Medicinal Chemistry},
volume = {65},
number = {22},
pages = {15014–15027},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mazola, Yuliet; Montesinos, José C. E. Márquez; Ramírez, David; Zúñiga, Leandro; Decher, Niels; Ravens, Ursula; Yarov-Yarovoy, Vladimir; González, Wendy
Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach Artículo de revista
En: Pharmaceutics, vol. 14, no 7, pp. 1356, 2022, ISSN: 1999-4923.
@article{mazola_common_2022,
title = {Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach},
author = {Yuliet Mazola and José C. E. Márquez Montesinos and David Ramírez and Leandro Zúñiga and Niels Decher and Ursula Ravens and Vladimir Yarov-Yarovoy and Wendy González},
url = {https://www.mdpi.com/1999-4923/14/7/1356},
doi = {10.3390/pharmaceutics14071356},
issn = {1999-4923},
year = {2022},
date = {2022-06-01},
urldate = {2024-12-14},
journal = {Pharmaceutics},
volume = {14},
number = {7},
pages = {1356},
abstract = {Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that a combined blockade of Nav1.5 (and its current, INa) and Kv1.5 (and its current, IKur) ion channels yield a synergistic anti-arrhythmic effect without alterations in ventricles. We focused on Kv1.5 and Nav1.5 to search for structural similarities in their binding site (BS) for flecainide (a common blocker and widely prescribed AAD) as a first step for prospective rational multi-target directed ligand (MTDL) design strategies. We present a computational workflow for a flecainide BS comparison in a flecainide-Kv1.5 docking model and a solved structure of the flecainide-Nav1.5 complex. The workflow includes docking, molecular dynamics, BS characterization and pattern matching. We identified a common structural pattern in flecainide BS for these channels. The latter belongs to the central cavity and consists of a hydrophobic patch and a polar region, involving residues from the S6 helix and P-loop. Since the rational MTDL design for AF is still incipient, our findings could advance multi-target atrial-selective strategies for AF treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that a combined blockade of Nav1.5 (and its current, INa) and Kv1.5 (and its current, IKur) ion channels yield a synergistic anti-arrhythmic effect without alterations in ventricles. We focused on Kv1.5 and Nav1.5 to search for structural similarities in their binding site (BS) for flecainide (a common blocker and widely prescribed AAD) as a first step for prospective rational multi-target directed ligand (MTDL) design strategies. We present a computational workflow for a flecainide BS comparison in a flecainide-Kv1.5 docking model and a solved structure of the flecainide-Nav1.5 complex. The workflow includes docking, molecular dynamics, BS characterization and pattern matching. We identified a common structural pattern in flecainide BS for these channels. The latter belongs to the central cavity and consists of a hydrophobic patch and a polar region, involving residues from the S6 helix and P-loop. Since the rational MTDL design for AF is still incipient, our findings could advance multi-target atrial-selective strategies for AF treatment.
