Hydroxychloroquine action on sodium Nav 1.5 from humans: implications for the treatment of COVID-19

• Grant number: 20/09403-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2021
• End date: May 31, 2022
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Danilo Roman Campos
• Grantee: Jaqueline Oliveira Sarmento
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The main function of the heart is maintained by the proper coupling of its electrical and mechanical activities, a process in which transmembrane ion channels are crucial. Among them, the channels for sodium, Nav1. 5 (main channel for cardiac sodium), encoded by the SCN5A gene, is an important regulator of cardiac myocyte excitability and, therefore, is commonly involved in cardiotoxicity events of drugs used in therapy. Polymorphisms resulting from the substitution of a single amino acid in the DNA sequences of these channels can alter its biophysical properties and alter the sensitivity of Nav1.5 to the substances that act on it, increasing or reducing the cardiotoxicity of drugs. The S1103Y, S524Y, R1193Q, and V1951L polymorphisms are the most common found and are important in the national scenario, as they are the majority in ethnic groups of great representation in Brazil. COVID-19 disease, caused by the coronavirus of severe acute respiratory syndrome 2, has had major impacts on public health worldwide. There is no effective therapy for the disease, and hydroxychloroquine has been shown to be a potential candidate for the treatment of symptoms. However, such a substance may have a cardiotoxic effect due to mechanisms that are not yet fully known, and that there is the action of such a compound on Nav 1.5. Thus, we aim to investigate: (1) the effect of hydroxychloroquine on the electrophysiological properties of human Nav1.5 channels; (2) if polymorphisms in the sodium channels alter the sensitivity of Nav1.5 to hydroxychloroquine, for both cases the Patch-Clamp technique and heterologous expression system will be used. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE V.; SARMENTO, JAQUELINE O.; COSTA, ALEXANDRE D.; SOARES, ALLYSSON T. C.; MACHADO, FABIANA S.; CRUZ, JADER S.; ROMAN-CAMPOS, DANILO. A novel substrate for arrhythmias in Chagas disease. PLoS Neglected Tropical Diseases, v. 15, n. 6, JUN 2021. (19/21304-4, 14/09861-1, 18/20777-3, 18/22830-9, 20/09403-4)

DA SILVA, MARIA VITORIA; SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE, V; SOUZA, DIEGO SANTOS; MARQUES, LEISIANE PEREIRA; SARMENTO, JAQUELINE OLIVEIRA; BESERRA, SAMUEL SANTOS; ROMAN-CAMPOS, DANILO. The insecticide beta-Cyfluthrin induces acute arrhythmic cardiotoxicity through interaction with NaV1.5 and ranolazine reverses the phenotype. Clinical Science, v. 136, n. 5, p. 15-pg., 2022-03-01. (21/05584-7, 19/18918-0, 18/20777-3, 18/22830-9, 20/09403-4, 19/21304-4)