Molnupiravir, a ribonucleoside antiviral prodrug against SARS-CoV-2, alters the voltage-gated sodium current and causes adverse events

Ai-Li Shiau; Kuan-Hsien Lee; Hsin-Yen Cho; Tzu-Hsien Chuang; Meng-Cheng Yu; Chao-Liang Wu; Sheng-Nan Wu

doi:10.1016/j.virol.2023.109865

Molnupiravir, a ribonucleoside antiviral prodrug against SARS-CoV-2, alters the voltage-gated sodium current and causes adverse events

Virology. 2023 Oct:587:109865. doi: 10.1016/j.virol.2023.109865. Epub 2023 Aug 7.

Authors

Ai-Li Shiau¹, Kuan-Hsien Lee², Hsin-Yen Cho³, Tzu-Hsien Chuang³, Meng-Cheng Yu³, Chao-Liang Wu⁴, Sheng-Nan Wu⁵

Affiliations

¹ Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, 60002, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
² Department of Emergency Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, 60002, Taiwan.
³ Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
⁴ Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, 60002, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan. Electronic address: wumolbio@mail.ncku.edu.tw.
⁵ Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan. Electronic address: snwu@mail.ncku.edu.tw.

PMID: 37572519
DOI: 10.1016/j.virol.2023.109865

Abstract

Molnupiravir (MOL) is a ribonucleoside prodrug for oral treatment of COVID-19. Common adverse effects of MOL are headache, diarrhea, and nausea, which may be associated with altered sodium channel function. Here, we investigated the effect of MOL on voltage-gated Na⁺ current (I_Na) in pituitary GH₃ cells. We show that MOL had distinct effects on transient and late I_Na, in combination with decreased time constant in the slow component of I_Na inactivation. The 50% inhibitory concentration (IC₅₀) values of MOL for suppressing transient and late I_Na were 26.1 and 6.3 μM, respectively. The overall steady-state current-voltage relationship of I_Na remained unchanged upon MOL exposure. MOL-induced alteration of I_Na may lead to changes in physiological function through sodium channels. Apart from its effect on inhibiting RNA virus replication, MOL exerts inhibitory effects on plasmalemma I_Na, which might constitute an additional yet crucial underlying mechanism of its pharmacological activity or adverse events.

Keywords: Adverse effect; Antiviral drug; COVID-19; Late Na(+) current; Molnupiravir (EIDD-2801, MK-4482); Resurgent Na(+) current; SARS-CoV-2; Sodium channel; Voltage-gated Na(+) current.