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Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.掩蔽型丙氨酰双脱氧胸苷单磷酸衍生物的抗HIV作用机制
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7295-9. doi: 10.1073/pnas.93.14.7295.
2
Antiretrovirus specificity and intracellular metabolism of 2',3' -didehydro-2',3'-dideoxythymidine (stavudine) and its 5'-monophosphate triester prodrug So324.
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3
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cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system.环胞嘧啶-2',3'-二脱氧-2',3'-二脱氢胸苷一磷酸（环胞嘧啶-d4TMP）：一种新型d4TMP递送系统的合成与抗病毒评估
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本文引用的文献

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Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite.司他夫定的芳基磷酰胺酯衍生物在组织培养中具有更高的抗HIV效力，可能是通过产生一种新的细胞内代谢产物发挥作用。
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Certain phosphoramidate derivatives of dideoxy uridine (ddU) are active against HIV and successfully by-pass thymidine kinase.某些双脱氧尿苷（ddU）的磷酰胺酸酯衍生物对HIV具有活性，并成功绕过胸苷激酶。
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The anti-HTLV-III (anti-HIV) and cytotoxic activity of 2',3'-didehydro-2',3'-dideoxyribonucleosides: a comparison with their parental 2',3'-dideoxyribonucleosides.2',3'-二脱氢-2',3'-二脱氧核糖核苷的抗HTLV-III（抗HIV）及细胞毒性活性：与其母体2',3'-二脱氧核糖核苷的比较
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Initial studies on the cellular pharmacology of 2',3'-dideoxyinosine, an inhibitor of HIV infectivity.对2',3'-双脱氧肌苷（一种HIV感染性抑制剂）的细胞药理学的初步研究。
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Anti-retrovirus activity of 3'-fluoro- and 3'-azido-substituted pyrimidine 2',3'-dideoxynucleoside analogues.3'-氟代和3'-叠氮基取代的嘧啶2',3'-二脱氧核苷类似物的抗逆转录病毒活性
Biochem Pharmacol. 1988 Jul 15;37(14):2847-56. doi: 10.1016/0006-2952(88)90049-4.
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Phosphorylation of 2',3'-dideoxyinosine by cytosolic 5'-nucleotidase of human lymphoid cells.人淋巴细胞胞质5'-核苷酸酶对2',3'-二脱氧肌苷的磷酸化作用。
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Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-human immunodeficiency virus compounds.两种强效抗人类免疫缺陷病毒化合物2'，3'-二脱氢-2'，3'-二脱氧胸苷和3'-叠氮基-2'，3'-二脱氧胸苷的细胞内代谢差异模式。
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掩蔽型丙氨酰双脱氧胸苷单磷酸衍生物的抗HIV作用机制

Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.

作者信息

Balzarini J, Karlsson A, Aquaro S, Perno C F, Cahard D, Naesens L, De Clercq E, McGuigan C

机构信息

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

出版信息

Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7295-9. doi: 10.1073/pnas.93.14.7295.

DOI:10.1073/pnas.93.14.7295
PMID:8692986
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC38977/
Abstract

So324 is a 2',3'-dideoxy-2',3'-didehydrothymidine-5'-monophosphate (d4T-MP) prodrug containing at the phosphate moiety a phenyl group and the methylester of alanine linked to the phosphate through a phosphoramidate linkage. So324 has anti-HIV activity in human CEM, MT4, and monocyte/macrophage cells that is superior to that of d4T. In contrast to d4T, So324 is also able to inhibit HIV replication in thymidine kinase-deficient CEM cells. After uptake of So324 by intact human lymphocytes, d4T-MP is released and subsequently converted intracellularly to d4T-TP. In addition, accumulation of substantial amounts of a novel d4T derivative has been found. This d4T metabolite has been characterized as alaninyl d4T-MP. The latter metabolite accumulates at approximately 13- to 200-fold higher levels than d4T-TP depending the experimental conditions. Alaninyl d4T-MP should be considered as an intra- and/or extracellular depot form of d4T and/or d4T-MP. These findings may explain the superior anti-retroviral activity of So324 over d4T in cell culture.

摘要

So324是一种2',3'-二脱氧-2',3'-二脱氢胸苷-5'-单磷酸（d4T-MP）前药，其磷酸部分含有一个苯基以及通过氨基磷酸酯键与磷酸相连的丙氨酸甲酯。So324在人CEM、MT4以及单核细胞/巨噬细胞中具有抗HIV活性，且优于d4T。与d4T不同的是，So324还能够抑制胸苷激酶缺陷的CEM细胞中的HIV复制。完整的人淋巴细胞摄取So324后，d4T-MP被释放出来，随后在细胞内转化为d4T-TP。此外，还发现了大量新型d4T衍生物的积累。这种d4T代谢产物已被鉴定为丙氨酰d4T-MP。根据实验条件，后一种代谢产物的积累水平比d4T-TP高约13至200倍。丙氨酰d4T-MP应被视为d4T和/或d4T-MP的细胞内和/或细胞外储存形式。这些发现可能解释了So324在细胞培养中比d4T具有更强的抗逆转录病毒活性。