Evidence for the Effectiveness of Remdesivir (GS-5734), a Nucleoside-Analog Antiviral Drug in the Inhibition of I K(M) or I K(DR) and in the Stimulation of I MEP.

Wei-Ting Chang,Zi-Han Gao,Shih-Wei Lee,Wen-Kai Lee,Ping-Yen Liu,Sheng-Nan Wu

doi:10.3389/fphar.2020.01091

Abstract

Remdesivir (RDV, GS-5734), a broad-spectrum antiviral drug in the class of nucleotide analogs, has been particularly tailored for treatment of coronavirus infections. However, to which extent RDV is able to modify various types of membrane ion currents remains largely uncertain. In this study, we hence intended to explore the possible perturbations of RDV on ionic currents endogenous in pituitary GH3 cells and Jurkat T-lymphocytes. The whole-cell current recordings of ours disclosed that upon membrane depolarization in GH3 cells the exposure to RDV concentration-dependently depressed the peak or late components of I K(DR) elicitation with effective IC50 values of 10.1 or 2.8 μM, respectively; meanwhile, the value of dissociation constant of RDV-induced blockage of I K(DR) on the basis of the first-order reaction was yielded to be 3.04 μM. Upon the existence of RDV, the steady-state inactivation curve of I K(DR) was established in the RDV presence; moreover, the recovery became slowed. However, RDV-induced blockage of I K(DR) failed to be overcome by further addition of either α,β-methylene ATP or cyclopentyl-1,3-dipropylxanthine. The RDV addition also lessened the strength of M-type K+ current with the IC50 value of 2.5 μM. The magnitude of voltage hysteresis of I K(M) elicited by long-lasting triangular ramp pulse was diminished by adding RDV. Membrane electroporation-induced current in response to large hyperpolarization was enhanced, with an EC50 value of 5.8 μM. Likewise, in Jurkat T-lymphocytes, adding RDV declined I K(DR) amplitude concomitantly with the raised rate of current inactivation applied by step depolarization. Therefore, in terms of the RDV molecule, there appears to be an unintended activity of the prodrug on ion channels. Its inhibition of both I K(DR) and I K(M) occurring in a non-genomic fashion might provide additional but important mechanisms through which in vivo cellular functions are seriously perturbed.

Highlights

Remdesivir (RDV, GS-5734), a broad-spectrum antiviral agent, is recognized as a mono-phosphoramidate prodrug of an adenosine analog that metabolizes into its active form GS441524 which is a C-adenosine nucleoside analog (Warren et al, 2016; Lo et al, 2017; Sheahan et al, 2017; Tchesnokov et al, 2019; Gordon et al, 2020)
Depending on the modified Hill equation elaborated in Materials and Methods section, the concentration required for half-maximal inhibition (IC50) value entailed for its inhibitory effects on initial peak or late components of IK(DR) was yielded to be 10.1 or 2.8 mM, respectively (Figure 1B)
The suppression of RDV on IK(DR) is associated with an increasing inactivation rate of the current responding to membrane depolarization

Summary

Introduction

Remdesivir (RDV, GS-5734), a broad-spectrum antiviral agent, is recognized as a mono-phosphoramidate prodrug of an adenosine analog that metabolizes into its active form GS441524 which is a C-adenosine nucleoside analog (Warren et al, 2016; Lo et al, 2017; Sheahan et al, 2017; Tchesnokov et al, 2019; Gordon et al, 2020) This compound, a nucleotideanalog inhibitor of RNA-dependent RNA polymerase, is thought to be highly active against coronaviruses (CoVs), including MERS-Cov and SARS-CoV-2 None of the noticeable studies have been available with regard to the perturbing actions of RDV on membrane ion channels

Methods

Results

Conclusion