Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19
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 d...
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| Format: | Article |
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MDPI AG
2021-07-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/13/7/1369 |
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| author | Henrik Berg Rasmussen Gesche Jürgens Ragnar Thomsen Olivier Taboureau Kornelius Zeth Poul Erik Hansen Peter Riis Hansen |
| author_facet | Henrik Berg Rasmussen Gesche Jürgens Ragnar Thomsen Olivier Taboureau Kornelius Zeth Poul Erik Hansen Peter Riis Hansen |
| author_sort | Henrik Berg Rasmussen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T09:19:28Z |
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| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T09:19:28Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-15d61dbd3e404e23840e2bbba81147ee2023-11-22T05:14:55ZengMDPI AGViruses1999-49152021-07-01137136910.3390/v13071369Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19Henrik Berg Rasmussen0Gesche Jürgens1Ragnar Thomsen2Olivier Taboureau3Kornelius Zeth4Poul Erik Hansen5Peter Riis Hansen6Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, DK-4000 Roskilde, DenmarkClinical Pharmacology Unit, Zealand University Hospital, DK-4000 Roskilde, DenmarkSection of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, DK-2100 Copenhagen, DenmarkINSERM U1133, CNRS UMR 8251, Université de Paris, F-75013 Paris, FranceDepartment of Science and Environment, Roskilde University Center, DK-4000 Roskilde, DenmarkDepartment of Science and Environment, Roskilde University Center, DK-4000 Roskilde, DenmarkDepartment of Cardiology, Herlev and Gentofte Hospital, DK-2900 Hellerup, DenmarkGS-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.https://www.mdpi.com/1999-4915/13/7/1369GS-441524adenosine analogsCOVID-19adenosine transportersadenosine kinaseadenosine levels |
| spellingShingle | Henrik Berg Rasmussen Gesche Jürgens Ragnar Thomsen Olivier Taboureau Kornelius Zeth Poul Erik Hansen Peter Riis Hansen Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19 Viruses GS-441524 adenosine analogs COVID-19 adenosine transporters adenosine kinase adenosine levels |
| title | Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19 |
| title_full | Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19 |
| title_fullStr | Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19 |
| title_full_unstemmed | Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19 |
| title_short | Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19 |
| title_sort | cellular uptake and intracellular phosphorylation of gs 441524 implications for its effectiveness against covid 19 |
| topic | GS-441524 adenosine analogs COVID-19 adenosine transporters adenosine kinase adenosine levels |
| url | https://www.mdpi.com/1999-4915/13/7/1369 |
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