Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Abstract

To overcome the many hurdles preventing the use of antiviral and anticancer nucleosides as therapeutics, the development of a prodrug methodology (i.e., pronucleotide) for the in vivo delivery of nucleotides has been proposed as a solution. The ideal pronucleotide should be non‐toxic, stable in plasma and blood, capable of being i.v. and/or orally dosed, and intracellularly convertible to the corresponding nucleotide. Although this goal has yet to be achieved, many clever and imaginative pronucleotide approaches have been developed, which are likely to be important pharmacological tools. This review will discuss the major advances and future directions of the emerging field of antiviral and anticancer pronucleotide design and development. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 6, 417–451, 2000

Histidine Triad Nucleotide-binding Protein 1 (HINT-1) Phosphoramidase Transforms Nucleoside 5′-O-Phosphorothioates to Nucleoside 5′-O-Phosphates

“…In the prodrug approach, such molecules are converted intracellularly to the corresponding nucleoside 5Ј-monophosphates (17). It is believed that the enzyme responsible for hydrolysis of the P-N bond in both classes of nucleotide phosphoramidates is histidine triad nucleotide-binding protein 1 (Hint-1) (14,18). The Hint-1 protein is a member of the histidine triad (HIT) protein superfamily.…”

31P NMR and Genetic Analysis Establish hinT as the Only Escherchia coli Purine Nucleoside Phosphoramidase and as Essential for Growth under High Salt Conditions

“…Part of the reason for continued interest in phosphoramidates has been their demonstrated utility as prodrugs of antiviral and anticancer nucleoside monophosphates or as pronucleo-tides (21)(22)(23)(24)(25). Typically, therapeutic nucleosides must be converted to the corresponding mono-, di-, and triphosphates before exhibiting biological activity.…”

“…Nevertheless, many nucleosides are poor substrates for endogenous nucleoside kinases. To overcome this hurdle, several pronucleotide approaches have been investigated, including the use of nucleoside monophosphoramidates (24,26).…”

Improved antiviral activity of the aryloxymethoxyalaninyl phosphoramidate (APA) prodrug of abacavir (ABC) is due to the formation of markedly increased carbovir 5′‐triphosphate metabolite levels

“…Examples of a relatively poor conversion rate by the activating enzyme other than ABC are stavudine (d4T) by thymidine kinase (TK) [7,8], zalcitabine (ddC) by 2 0 -deoxycytidine kinase [9,10], and didanosine (ddI) by 5 0 -nucleotidase [4,5]. Therefore, several attempts have been undertaken to deliver activated (phosphorylated) nucleoside analogues directly into the virusinfected target cells [11][12][13][14][15][16][17][18][19][20][21][22][23][24]. One of these approaches has proven very successful when applied on thymidine analogues such as d4T.…”