tetano
Editor, Senior Moderator
Front Pharmacol
. 2020 Jul 21;11:1091.
doi: 10.3389/fphar.2020.01091. eCollection 2020.
Evidence for the Effectiveness of Remdesivir (GS-5734), a Nucleoside-Analog Antiviral Drug in the Inhibition of I [SUB]K(M)[/SUB] or I [SUB]K(DR)[/SUB] and in the Stimulation of I [SUB]MEP[/SUB]
Wei-Ting Chang[SUP] 1 2 3 [/SUP], Ping-Yen Liu[SUP] 3 4 [/SUP], Zi-Han Gao[SUP] 5 [/SUP], Shih-Wei Lee[SUP] 5 [/SUP], Wen-Kai Lee[SUP] 5 [/SUP], Sheng-Nan Wu[SUP] 5 6 7 [/SUP]
Affiliations
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 GH[SUB]3[/SUB] cells and Jurkat T-lymphocytes. The whole-cell current recordings of ours disclosed that upon membrane depolarization in GH[SUB]3[/SUB] cells the exposure to RDV concentration-dependently depressed the peak or late components of I [SUB]K(DR)[/SUB] elicitation with effective IC[SUB]50[/SUB] values of 10.1 or 2.8 μM, respectively; meanwhile, the value of dissociation constant of RDV-induced blockage of I [SUB]K(DR)[/SUB] 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 [SUB]K(DR)[/SUB] was established in the RDV presence; moreover, the recovery became slowed. However, RDV-induced blockage of I [SUB]K(DR)[/SUB] 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[SUP]+[/SUP] current with the IC[SUB]50[/SUB] value of 2.5 μM. The magnitude of voltage hysteresis of I [SUB]K(M)[/SUB] 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 EC[SUB]50[/SUB] value of 5.8 μM. Likewise, in Jurkat T-lymphocytes, adding RDV declined I [SUB]K(DR)[/SUB] 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 [SUB]K(DR)[/SUB] and I [SUB]K(M)[/SUB] occurring in a non-genomic fashion might provide additional but important mechanisms through which in vivo cellular functions are seriously perturbed.
Keywords: M-type K+ current; delayed-rectifier K+ current; electroporation-induced current; lymphocyte; pituitary cell; remdesivir (GS-5734); voltage hysteresis.
. 2020 Jul 21;11:1091.
doi: 10.3389/fphar.2020.01091. eCollection 2020.
Evidence for the Effectiveness of Remdesivir (GS-5734), a Nucleoside-Analog Antiviral Drug in the Inhibition of I [SUB]K(M)[/SUB] or I [SUB]K(DR)[/SUB] and in the Stimulation of I [SUB]MEP[/SUB]
Wei-Ting Chang[SUP] 1 2 3 [/SUP], Ping-Yen Liu[SUP] 3 4 [/SUP], Zi-Han Gao[SUP] 5 [/SUP], Shih-Wei Lee[SUP] 5 [/SUP], Wen-Kai Lee[SUP] 5 [/SUP], Sheng-Nan Wu[SUP] 5 6 7 [/SUP]
Affiliations
- PMID: 32792942
- PMCID: PMC7385287
- 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 GH[SUB]3[/SUB] cells and Jurkat T-lymphocytes. The whole-cell current recordings of ours disclosed that upon membrane depolarization in GH[SUB]3[/SUB] cells the exposure to RDV concentration-dependently depressed the peak or late components of I [SUB]K(DR)[/SUB] elicitation with effective IC[SUB]50[/SUB] values of 10.1 or 2.8 μM, respectively; meanwhile, the value of dissociation constant of RDV-induced blockage of I [SUB]K(DR)[/SUB] 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 [SUB]K(DR)[/SUB] was established in the RDV presence; moreover, the recovery became slowed. However, RDV-induced blockage of I [SUB]K(DR)[/SUB] 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[SUP]+[/SUP] current with the IC[SUB]50[/SUB] value of 2.5 μM. The magnitude of voltage hysteresis of I [SUB]K(M)[/SUB] 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 EC[SUB]50[/SUB] value of 5.8 μM. Likewise, in Jurkat T-lymphocytes, adding RDV declined I [SUB]K(DR)[/SUB] 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 [SUB]K(DR)[/SUB] and I [SUB]K(M)[/SUB] occurring in a non-genomic fashion might provide additional but important mechanisms through which in vivo cellular functions are seriously perturbed.
Keywords: M-type K+ current; delayed-rectifier K+ current; electroporation-induced current; lymphocyte; pituitary cell; remdesivir (GS-5734); voltage hysteresis.