“…To improve cell permeability and pharmacokinetic performance, nucleoside/nucleotide analogs are often structurally modified to be ester prodrugs [2]. The ProTide technology has been a powerful tool to improve the cell permeability and the intracellular activation of nucleoside/nucleotide antivirals and anticancer drugs [3,4]. The most recent ProTide technology is to structurally modify nucleoside/nucleotide analogs to aryloxy phosphoramidite prodrugs by masking two of the oxygens of the monophosphate and monophosphonate groups with an aryloxy group and an amino acid ester group.…”
ProTide technology is a powerful tool for the design of nucleoside/nucleotide analog prodrugs. ProTide prodrug design improves cell permeability and enhances intracellular activation. The hydrolysis of the ester bond of a ProTide is a determinant of the intracellular activation efficiency and final antiviral efficacy of the prodrug. The hydrolysis is dictated by the catalytic activity and abundance of activating enzymes. The antiviral agents tenofovir alafenamide (TAF) and sofosbuvir (SBV) are typical ProTides. Both TAF and SBV have also been proposed to treat patients with COVID-19. However, the mechanisms underlying the activation of the two prodrugs in the lung remain inconclusive. In the present study, we profiled the catalytic activity of serine hydrolases in human lung S9 fractions using an activity-based protein profiling assay. We evaluated the hydrolysis of TAF and SBV using human lung and liver S9 fractions and purified enzymes. The results showed that CatA and CES1 were involved in the hydrolysis of the two prodrugs in the human lung. More specifically, CatA exhibited a nearly 4-fold higher hydrolytic activity towards TAF than SBV, whereas the CES1 activity on hydrolyzing TAF was slightly lower than that for SBV. Overall, TAF had a nearly 4-fold higher hydrolysis rate in human lung S9 than SBV. We further analyzed protein expression levels of CatA and CES1 in the human lung, liver, and primary cells of the two tissues using proteomics data extracted from the literature. The relative protein abundance of CatA to CES1 was considerably higher in the human lung and primary human airway epithelial cells than in the human liver and primary human hepatocytes. The findings demonstrated that the high susceptivity of TAF to CatA-mediated hydrolysis resulted in efficient TAF hydrolysis in the human lung, suggesting that CatA could be utilized as a target activating enzyme when designing antiviral ester prodrugs for the treatment of respiratory virus infection.
“…To improve cell permeability and pharmacokinetic performance, nucleoside/nucleotide analogs are often structurally modified to be ester prodrugs [2]. The ProTide technology has been a powerful tool to improve the cell permeability and the intracellular activation of nucleoside/nucleotide antivirals and anticancer drugs [3,4]. The most recent ProTide technology is to structurally modify nucleoside/nucleotide analogs to aryloxy phosphoramidite prodrugs by masking two of the oxygens of the monophosphate and monophosphonate groups with an aryloxy group and an amino acid ester group.…”
ProTide technology is a powerful tool for the design of nucleoside/nucleotide analog prodrugs. ProTide prodrug design improves cell permeability and enhances intracellular activation. The hydrolysis of the ester bond of a ProTide is a determinant of the intracellular activation efficiency and final antiviral efficacy of the prodrug. The hydrolysis is dictated by the catalytic activity and abundance of activating enzymes. The antiviral agents tenofovir alafenamide (TAF) and sofosbuvir (SBV) are typical ProTides. Both TAF and SBV have also been proposed to treat patients with COVID-19. However, the mechanisms underlying the activation of the two prodrugs in the lung remain inconclusive. In the present study, we profiled the catalytic activity of serine hydrolases in human lung S9 fractions using an activity-based protein profiling assay. We evaluated the hydrolysis of TAF and SBV using human lung and liver S9 fractions and purified enzymes. The results showed that CatA and CES1 were involved in the hydrolysis of the two prodrugs in the human lung. More specifically, CatA exhibited a nearly 4-fold higher hydrolytic activity towards TAF than SBV, whereas the CES1 activity on hydrolyzing TAF was slightly lower than that for SBV. Overall, TAF had a nearly 4-fold higher hydrolysis rate in human lung S9 than SBV. We further analyzed protein expression levels of CatA and CES1 in the human lung, liver, and primary cells of the two tissues using proteomics data extracted from the literature. The relative protein abundance of CatA to CES1 was considerably higher in the human lung and primary human airway epithelial cells than in the human liver and primary human hepatocytes. The findings demonstrated that the high susceptivity of TAF to CatA-mediated hydrolysis resulted in efficient TAF hydrolysis in the human lung, suggesting that CatA could be utilized as a target activating enzyme when designing antiviral ester prodrugs for the treatment of respiratory virus infection.
“…Many prodrugs of tenofovir such as TDF were subsequently developed to enhance the permeability across the intestinal wall 33 . For instance, phosphoramidate prodrugs of tenofovir could be designed by the “ProTide” strategy that offers the efficient intracellular delivery of monophosphates and monophosphonates of nucleoside analogues across the cell membrane by passive diffusion 34 , 35 . Figure 3 Discovery and metabolic pathway of tenofovir alafenamide.…”
“…This compound is then hydrolyzed by an amidase, Although nucleoside derivatives generally act in di-or triphosphate form, these species are not employed as such because of their high polarity, which hampers their absorption across cell membranes. Phosphoramidates and related prodrugs, developed by McGuigan, are generally described as ProTide (PROdrug + nucleoTIDE), and have found widespread application in recent years [40]. The ionizable groups of these compounds are blocked by lipophilic moieties, allowing a good membrane permeability.…”
In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.
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