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

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 3 cells and Jurkat T-lymphocytes. The whole-cell current recordings of ours disclosed that upon membrane depolarization in GH 3 cells the exposure to RDV concentration-dependently depressed the peak or late components of I K(DR) elicitation with effective IC 50 values of 10.1 or 2.8 mM, 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 mM. 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 a,b-methylene ATP or cyclopentyl-1,3dipropylxanthine. The RDV addition also lessened the strength of M-type K + current with the IC 50 value of 2.5 mM. The magnitude of voltage hysteresis of I K(M) elicited by longlasting triangular ramp pulse was diminished by adding RDV. Membrane electroporationinduced current in response to large hyperpolarization was enhanced, with an EC 50 value of 5.8 mM. 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

High Capability of Pentagalloylglucose (PGG) in Inhibiting Multiple Types of Membrane Ionic Currents

“…In these whole-cell measurements, we bathed cells in high-K + , Ca 2+ -free solution, and the electrode was filled up with K + -containing solution. The examined cell was maintained at −10 mV and a series of voltage steps ranging between −100 and −10 mV were delivered to evoke deactivating I K(erg) [ 18 , 28 ]. Any effects on I K(erg) density did not occur, as the cells were exposed to PGG (3 μM).…”

“…The voltage-gated K + (K V ) channels are crucial in determining membrane excitability in electrically excitable or even non-excitable cells [ 16 , 17 , 18 ]. Noticeably, K V 3 ( KCNC ) and K V 2 ( KCNB ) channels constitute two types of delayed-rectifier K + currents ( I K(DR) ), and they are widespread in different excitable cells that include endocrine cells [ 18 , 19 , 20 , 21 ].…”

“…The voltage-gated K + (K V ) channels are crucial in determining membrane excitability in electrically excitable or even non-excitable cells [ 16 , 17 , 18 ]. Noticeably, K V 3 ( KCNC ) and K V 2 ( KCNB ) channels constitute two types of delayed-rectifier K + currents ( I K(DR) ), and they are widespread in different excitable cells that include endocrine cells [ 18 , 19 , 20 , 21 ]. The biophysical properties of K V 3.1-K V 3.2 channels, which are the dominant factors of I K(DR) identified in pituitary tumor (GH 3 ) cells, are characterized by a positively shifted voltage dependency as well as by fast deactivation rate of the current [ 19 , 20 , 22 ].…”

Biochemical features and mutations of key proteins in SARS-CoV-2 and their impacts on RNA therapeutics

“…Remdesivir has drawn great attention as it is the first and only small molecule drug approved by the U.S. FDA to specifically treat COVID-19 patients. As an adenosine analog, remdesivir was initially developed to treat infection of another coronavirus, Ebola [78] , [79] , [80] . Remdesivir binds to the binding pocket of RdRp and terminates RdRp-dependent viral RNA synthesis [81] , [82] .…”

Analytical methods for the determination of remdesivir as a promising antiviral candidate drug for the COVID-19 pandemic

“…One of these drugs is remdesivir, an RdRP inhibitor, which shows a broad spectrum of antiviral activity against many RNA viruses like Ebola virus, Marburg, MERS-CoV, SARS-CoV, respiratory syncytial virus and Nipah virus in vivo and in vitro studies, and thus it is being studied for post-infection treatment for COVID-19 (9)(10)(11)(12). Human studies of the pharmacokineticpharmacodynamics relationship of remdesivir and Review its metabolite appeared necessary in the context of COVID-19.…”