Triphosphate and diphosphate nucleoside prodrugs: broadening the therapeutic potential of nucleoside-based treatments

Serpi, Michaela ORCID: https://orcid.org/0000-0002-6162-7910, Tisnerat, Camille, Krysa, Daniel and Pertusati, Fabrizio ORCID: https://orcid.org/0000-0003-4532-9101 2026. Triphosphate and diphosphate nucleoside prodrugs: broadening the therapeutic potential of nucleoside-based treatments. RSC Medicinal Chemistry 10.1039/d6md00584e

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Abstract

Multiple prodrug strategies have been developed to deliver nucleoside monophosphates (NMPs) and thereby overcome the initial kinase-mediated intracellular phosphorylation of nucleoside analogues (NAs), a major bottleneck in their activation. However, some NAs are limited by a second and/or third slow and inefficient phosphorylation step, which can lead to accumulation of mono- and diphosphate intermediates with associated toxicity. In addition, the metabolic pathways leading to the formation of the active nucleoside triphosphates remain poorly characterised for many reported analogues. Consequently, di- and triphosphate prodrug strategies for NAs have gained increasing attention in recent years. Here, we provide a comprehensive overview of the current approaches for development of these higher phosphorylated nucleotide analogues, including their activation pathways in different media, biological activity, synthetic methodologies, and their applicability across a broad range of NAs. Taken together, this review highlights both the potential of NDP and NTP prodrug strategies and the challenges associated with their development, providing a framework to guide future advances in their rational design and broader application.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Chemistry Schools > Physical, Chemical & Environmental Sciences
Publisher:	Royal Society of Chemistry (RSC)
ISSN:	2979-1065
Date of First Compliant Deposit:	20 October 2026
Date of Acceptance:	10 September 2026
Last Modified:	20 Oct 2026 11:45
URI:	https://orca.cardiff.ac.uk/id/eprint/190338

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