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首页> 外文期刊>Journal of Medicinal Chemistry >Reduction Sensitive Lipid Conjugates of Tenofovir: Synthesis, Stability, and Antiviral Activity
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Reduction Sensitive Lipid Conjugates of Tenofovir: Synthesis, Stability, and Antiviral Activity

机译：替诺福韦的还原敏感性脂质缀合物：合成，稳定性和抗病毒活性。

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摘要

The therapeutic value of numerous small molecules hinges on their ability to permeate the plasma membrane. This is particularly true for tenofovir (TFV), adefovir, and other antiviral nucleosides that demonstrate potent antiviral activity but poor bioavailability. Using TFV as a model substrate, we hybridized two disparate prodrug strategies to afford novel reduction-sensitive lipid conjugates of TFV that exhibit subnanomolar activity toward HIV-1 and are stable in human plasma for more than 24 h with a therapeutic index approaching 30000. These compounds significantly rival the clinically approved formulation of TFV and revitalize the potential of disulfide-bearing prodrugs which have seen limited in vitro and in vivo success since their debut over 20 years ago. We further demonstrate the utility of these conjugates as a tool to indirectly probe the enzymatic hydrolysis of phosphonomonoesters that may further advance the development of other prodrug strategies for nucleosides, peptides, and beyond.
机译：许多小分子的治疗价值取决于它们渗透质膜的能力。替诺福韦（TFV），阿德福韦和其他显示有效抗病毒活性但生物利用度较差的抗病毒核苷尤其如此。我们使用TFV作为模型底物，我们杂交了两种不同的前药策略，以提供新型的TFV还原敏感性脂质偶联物，它们对HIV-1表现出亚纳摩尔活性，并且在人血浆中稳定超过24小时，治疗指数接近30000。自20年前首次问世以来，这些化合物可与TFV的临床批准制剂显着匹敌，并重现了带有二硫键的前药的潜力，这些药物在体外和体内的成功均有限。我们进一步证明了这些缀合物作为间接探测膦酰基单酯的酶促水解的工具的实用性，该酶促水解可进一步促进核苷，肽等的其他前药策略的发展。

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