Abstract
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.
Highlights
Despite the emergence of vaccines for prevention of COVID-19, there is a continuing need for potent antiviral agents in the treatment of the disease
Remdesivir was originally developed for treatment of infections with RNA viruses possessing the potential to develop into pandemics such as Ebola virus disease [1], and received emergency approval for treatment of COVID-19 based on findings that it decreased mortality and shortened hospital stays [2]
It is possible that GS-441524 is more effective against early stages of COVID-19, i.e., before spreading of the virus to the lower airways has occurred, than later stages of the infection, since the majority of the transporters implicated in cellular uptake of adenosine analogs appear to be more abundantly expressed in the upper than lower airways
Summary
Despite the emergence of vaccines for prevention of COVID-19, there is a continuing need for potent antiviral agents in the treatment of the disease. Based on different procedures for viral quantification, one of these studies reported a half-maximal inhibitory concentration (IC50) value of 0.47 μM for the anti-SARSCoV-2 activity of GS-441524 in Vero cells, and IC50 values of 0.62 and 1.09 μM for its ability to inhibit this virus in the Calu-3 2B4 human lung cancer cell line [8]. GS-441524 was found to be highly effective in the treatment of feline infectious peritonitis caused by a feline coronavirus [10] This agent was reported to significantly inhibit SARS-CoV-2 in a mouse model [7]. We here discuss cellular uptake and intracellular phosphorylation of GS-441524 and based on this assess its effectiveness for treatment of COVID-19
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