Laux Wolfgang Hg, Priet Stéphane, Alvarez Karine, Peyrottes Suzanne, Périgaud Christian
1 131825 Institut des Biomolécules Max Mousseron (IBMM) , UMR 5247 CNRS, Univ. Montpellier, ENSCM, Campus Triolet, Montpellier, Cedex, France.
2 Laboratoire AFMB, AMU, CNRS, UMR 7257, Groupe ''Chimie Médicinale Antivirale'', Marseille, Cedex, France.
Antivir Chem Chemother. 2018 Jan-Dec;26:2040206618757636. doi: 10.1177/2040206618757636.
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 (IC = 403.0 ± 75.5 µM) and proved to be less effective than PMEApp (IC = 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.
背景 先前针对多种抗病毒核苷类似物（如齐多夫定和2'，3'-双脱氧核苷），研究了在5'-三磷酸核苷类似物的三磷酸链内用β，γ-膦酸酯部分取代β，γ-焦磷酸酯。因此，已表明这些化学修饰在某些情况下可保留三磷酸类似物对HIV逆转录酶（HIV-RT）的终止底物特性。在此，我们旨在基于著名的抗病毒药物9-[(2-膦酰甲氧基)乙基]腺嘌呤（PMEA，阿德福韦）的支架研究此类5'-三磷酸模拟物。方法 合成涉及PMEA的吗啉代衍生物与适当的焦磷酸类似物的偶联。与亲本核苷酸类似物（PMEApp）相比，在体外药敏试验中使用B亚型野生型HIV-1 RT测量所研究的二磷酸膦酸酯的掺入相对效率。结果 在寻找核苷5'-三磷酸模拟物时，我们合成并研究了一系列PMEA的二磷酸类似物，它们在磷原子之间带有不可水解的键。我们还比较了它们与亲本核苷酸类似物（PMEApp）对HIV-1逆转录酶的相对抑制能力。其中只有一种表现为弱抑制剂（IC = 403.0±75.5 μM），并且被证明比PMEApp（IC = 6.4±0.8 μM）效果更差。结论 PMEA二磷酸衍生物被设计为各种病毒聚合酶的潜在底物和/或抑制剂。这些修饰极大地影响了它们抑制HIV-RT的能力。
