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Efficient intracellular delivery of prodrugs with ProTides

ProTides are prodrugs allowing the efficient intracellular delivery of nucleoside analog monophosphates and monophosphonates. In ProTides the hydroxyls of the monophosphate or monophosphonate groups are masked by aromatic groups and amino acid ester moieties. In the cell, the amino acid ester groups are enzymatically cleaved-off to release the free nucleoside monophosphate and monophosphonate species.

Figure 1: Schematic structure of Protides.

Historically several nucleoside analogs were used for the treatment of various diseases including cancer and viral infections, and more than twenty different nucleoside analogs are now available for the treatment of viral infections and cancer. Inside the cell, nucleoside analogs nucleoside and nucleotide kinases activate the analogs. Kinases phosphorylate the nucleoside analogs in a stepwise manner to form physiologically active mono-, di-, and triphosphorylated metabolites.

For example, phosphinate and phosphate triester derivatives of the nucleoside analog arabinosyl adenosine (araA) inhibit DNA synthesis in mammalian cells. Their mode of action involves the release of the free nucleoside araA and the nucleotide araAMP.

As therapeutics, activated phosphorylated antiviral nucleoside analogs target and inhibit intracellular enzymes such as virus-encoded DNA or RNA polymerases. Additionally, they are incorporated into viral nucleic acid chains leading to the termination of the elongation process.

Different strategies are available for the synthesis of ProTides. Protide synthesis is possible by

1)  coupling of a nucleoside with a diarylphosphite followed by subsequent oxidative amination,

2)  coupling of the nucleoside with a phosphorochloridate reagent, or

3)  coupling of an amino acid to a nucleoside aryl phosphate.

Once inside the cell, ProTides utilize the metabolism of the cells to release the nucleoside monophosphate.

Reference

McGuigan C, Shackleton JM, Tollerfield SM, Riley PA. Synthesis and evaluation of some novel phosphate and phosphinate derivatives of araA. Studies on the mechanism of action of phosphate triesters. Nucleic Acids Res. 1989 Dec 25;17(24):10171-7. doi: 10.1093/nar/17.24.10171. PubMed PMID: 2602149; PubMed Central PMCID: PMC335291. [PMC]

Sarr A, Bré J, Um IH, Chan TH, Mullen P, Harrison DJ, Reynolds PA. Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031. Sci Rep. 2019 May 21;9(1):7643. doi: 10.1038/s41598-019-44089-3. PubMed PMID: 31113993; PubMed Central PMCID: PMC6529431. [PMC]

Wiki book   DNA and its nucleotides.

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