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Antivir Chem Chemother. 2018 Jan-Dec;26:2040206618757636. doi: 10.1177/2040206618757636.

Synthesis and substrate properties towards HIV-1 reverse transcriptase of new diphosphate analogues of 9-[(2-phosphonomethoxy)ethyl]adenine.

Author information

1
1 131825 Institut des Biomolécules Max Mousseron (IBMM) , UMR 5247 CNRS, Univ. Montpellier, ENSCM, Campus Triolet, Montpellier, Cedex, France.
2
2 Laboratoire AFMB, AMU, CNRS, UMR 7257, Groupe ''Chimie Médicinale Antivirale'', Marseille, Cedex, France.

Abstract

Background The replacement of β,γ-pyrophosphate by β,γ-phosphonate moieties within the triphosphate chain of 5'-triphosphate nucleoside analogues was previously studied for various antiviral nucleoside analogues such as AZT and 2',3'-dideoxynucleosides. Thus, it has been shown that these chemical modifications could preserve, in some cases, the terminating substrate properties of the triphosphate analogue for HIV-RT. Herein, we aimed to study such 5'-triphosphate mimics based on the scaffold of the well-known antiviral agent 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA, Adefovir). Methods Synthesis involved coupling of a morpholidate derivative of PMEA with appropriate pyrophosphoryl analogues. The relative efficiencies of incorporation of the studied diphosphate phosphonates were measured using subtype B WT HIV-1 RT in an in vitro susceptibility assay, in comparison to the parent nucleotide analogue (PMEApp). Results Searching for nucleoside 5'-triphosphate mimics, we have synthesized and studied a series of diphosphate analogues of PMEA bearing non hydrolysable bonds between the and phosphorus atoms. We also examined their relative inhibitory capacity towards HIV-1 reverse transcriptase in comparison to the parent nucleotide analogue (PMEApp). Only one of them appeared as a weak inhibitor (IC50 = 403.0 ± 75.5 µM) and proved to be less effective than PMEApp (IC50 = 6.4 ± 0.8 µM). Conclusion PMEA diphosphoryl derivatives were designed as potential substrates and/or inhibitors of various viral polymerases. These modifications dramatically affect their ability to inhibit HIV-RT.

KEYWORDS:

(phosphomethoxy)ethyl]adenine; HIV-1 reverse transcriptase; antiviral; phosphonate diphosphate analogues

PMID:
29436843
PMCID:
PMC5890543
DOI:
10.1177/2040206618757636
[Indexed for MEDLINE]
Free PMC Article

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