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Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19

1
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, DK-4000 Roskilde, Denmark
2
Department of Science and Environment, Roskilde University Center, DK-4000 Roskilde, Denmark
3
Clinical Pharmacology Unit, Zealand University Hospital, DK-4000 Roskilde, Denmark
4
Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark
5
INSERM U1133, CNRS UMR 8251, Université de Paris, F-75013 Paris, France
6
Department of Cardiology, Herlev and Gentofte Hospital, DK-2900 Hellerup, Denmark
*
Author to whom correspondence should be addressed.
Academic Editor: Albrecht von Brunn
Viruses 2021, 13(7), 1369; https://doi.org/10.3390/v13071369
Received: 17 May 2021 / Revised: 27 June 2021 / Accepted: 7 July 2021 / Published: 14 July 2021
(This article belongs to the Special Issue Broad-Spectrum Antivirals of Coronaviruses Replication)
GS-441524 is an adenosine analog and the parent nucleoside of the prodrug remdesivir, which has received emergency approval for treatment of COVID-19. Recently, GS-441524 has been proposed to be effective in the treatment of COVID-19, perhaps even being superior to remdesivir for treatment of this disease. Evaluation of the clinical effectiveness of GS-441524 requires understanding of its uptake and intracellular conversion to GS-441524 triphosphate, the active antiviral substance. We here discuss the potential impact of these pharmacokinetic steps of GS-441524 on the formation of its active antiviral substance and effectiveness for treatment of COVID-19. Available protein expression data suggest that several adenosine transporters are expressed at only low levels in the epithelial cells lining the alveoli in the lungs, i.e., the alveolar cells or pneumocytes from healthy lungs. This may limit uptake of GS-441524. Importantly, cellular uptake of GS-441524 may be reduced during hypoxia and inflammation due to decreased expression of adenosine transporters. Similarly, hypoxia and inflammation may lead to reduced expression of adenosine kinase, which is believed to convert GS-441524 to GS-441524 monophosphate, the perceived rate-limiting step in the intracellular formation of GS-441524 triphosphate. Moreover, increases in extracellular and intracellular levels of adenosine, which may occur during critical illnesses, has the potential to competitively decrease cellular uptake and phosphorylation of GS-441524. Taken together, tissue hypoxia and severe inflammation in COVID-19 may lead to reduced uptake and phosphorylation of GS-441524 with lowered therapeutic effectiveness as a potential outcome. Hypoxia may be particularly critical to the ability of GS-441524 to eliminate SARS-CoV-2 from tissues with low basal expression of adenosine transporters, such as alveolar cells. This knowledge may also be relevant to treatments with other antiviral adenosine analogs and anticancer adenosine analogs as well. View Full-Text
Keywords: GS-441524; adenosine analogs; COVID-19; adenosine transporters; adenosine kinase; adenosine levels GS-441524; adenosine analogs; COVID-19; adenosine transporters; adenosine kinase; adenosine levels
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MDPI and ACS Style

Rasmussen, H.B.; Jürgens, G.; Thomsen, R.; Taboureau, O.; Zeth, K.; Hansen, P.E.; Hansen, P.R. Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19. Viruses 2021, 13, 1369. https://doi.org/10.3390/v13071369

AMA Style

Rasmussen HB, Jürgens G, Thomsen R, Taboureau O, Zeth K, Hansen PE, Hansen PR. Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19. Viruses. 2021; 13(7):1369. https://doi.org/10.3390/v13071369

Chicago/Turabian Style

Rasmussen, Henrik B., Gesche Jürgens, Ragnar Thomsen, Olivier Taboureau, Kornelius Zeth, Poul E. Hansen, and Peter R. Hansen 2021. "Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19" Viruses 13, no. 7: 1369. https://doi.org/10.3390/v13071369

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