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Review
. 2018 Mar 22;61(6):2211-2226.
doi: 10.1021/acs.jmedchem.7b00734. Epub 2017 Aug 24.

The ProTide Prodrug Technology: From the Concept to the Clinic

Youcef Mehellou  1 , Hardeep S Rattan  2 , Jan Balzarini  3
Affiliations
Review

The ProTide Prodrug Technology: From the Concept to the Clinic

Youcef Mehellou et al. J Med Chem. .

Abstract

The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this approach, the hydroxyls of the monophosphate or monophosphonate groups are masked by an aromatic group and an amino acid ester moiety, which are enzymatically cleaved-off inside cells to release the free nucleoside monophosphate and monophosphonate species. Structurally, this represents the current end-point of an extensive medicinal chemistry endeavor that spans almost three decades. It started from the masking of nucleoside monophosphate and monophosphonate groups by simple alkyl groups and evolved into the sophisticated ProTide system as known today. This technology has been extensively employed in drug discovery, and it has already led to the discovery of two FDA-approved (antiviral) ProTides. In this work, we will review the development of the ProTide technology, its application in drug discovery, and its role in the improvement of drug delivery and efficacy.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Intracellular activation of therapeutic and experimental nucleoside analogues. NA: nucleoside analogue.
Figure 2
Figure 2
Chemical structures of therapeutic nucleoside analogue monophosphonates, cidofovir, adefovir, and tenofovir.
Figure 3
Figure 3
Chemical structures of the two FDA-approved antiviral ProTides, tenofovir alafenamide (TAF) and sofosbuvir.
Figure 4
Figure 4
Representation of the three main strategies for synthesizing ProTides. LG: leaving group. NA: nucleoside analogue. R: any ester. X: any aromatic substitution.
Figure 5
Figure 5
Synthetic strategies for accessing monophosphonate ProTides. AA: amino acid. NA: nucleoside analogue. R: any ester. X: any aromatic substitution. Y: O or CH2.
Figure 6
Figure 6
Postulated mechanism of ProTide metabolism illustrated using the ProTide of the anti-HIV agent d4T as an example.
Figure 7
Figure 7
Effect of the ester motif on the ProTides’ biological activity. The data presented regard d4T and its ProTides and were obtained from McGuigan et al.
Figure 8
Figure 8
Effect of the aryl group substitutions on the ProTides’ biological activity. The data presented regard d4T and its ProTides and were obtained from Siddiqui et al.
Figure 9
Figure 9
Effect of the amino acid on the ProTides’ biological activity. The data presented regard d4T and its ProTides and were obtained from McGuigan et al.
Figure 10
Figure 10
Chemical structures of key ProTides undergoing clinical trials.
See this image and copyright information in PMC

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