Inhibition of HIV-1 by octadecyloxyethyl esters of (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] nucleosides and evaluation of their mechanism of action.
Inhibition of HIV-1 by octadecyloxyethyl esters of (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] nucleosides and evaluation of their mechanism of action.
复制标题
(S)-[3-羟基-2-(膦酰甲氧基)丙基]核苷十八烷氧基乙基酯对 HIV-1 的抑制及其作用机制的评估。
DOI：
10.1128/aac.05161-11
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发表时间：
2011
影响因子：
4.9
通讯作者：
Evans,DavidH
中科院分区：
文献类型：
--
作者：
Magee,WendyC;Valiaeva,Nadejda;Beadle,JamesR;Richman,DouglasD;Hostetler,KarlY;Evans,DavidH
（S）-1-[3-羟基-2-（膦酰甲氧基）丙基]胞嘧啶（HPMPC [西多福韦]）和（S）-9-[3-羟基-2-（膦酰甲氧基）丙基]腺嘌呤（HPMPA）是多种DNA病毒的有效抑制剂。这些药物具有3′-羟基等价物，可以支持从掺入的药物分子的链延伸。最初报道HPMPC和HPMPA缺乏抗人类免疫缺陷病毒1型（HIV-1）的活性;最近的结果表明HPMPA的十八烷氧基乙基（ODE）和十六烷氧基丙基（HDP）酯是病毒的有效抑制剂。我们合成了一系列（S）-[3-羟基-2-（膦酰甲氧基）丙基]（HPMP）核苷的ODE酯，包括HPMPC、HPMP-鸟嘌呤（HPMPG）、HPMP-胸腺嘧啶（HPMPT）和HPMP-二氨基嘌呤（HPMPDAP），以及专性链终止剂（S）-9-[3-甲氧基-2-（膦酰甲氧基）丙基]腺嘌呤（MPMPA）的ODE酯。除ODE-HPMPT外，所有化合物在低纳摩尔浓度下均为HIV-1复制抑制剂。这些化合物也是HIV-1变异体复制的抑制剂，这些变异体对各种核苷逆转录酶（RT）抑制剂具有抗性，其浓度比预期的体内抑制浓度低几倍。为了探讨抗病毒活性的机制，HPMPC和HPMPA的活性代谢产物的HIV-1 RT催化的反应的影响进行了研究。HPMPC和HPMPA到DNA引物链的掺入导致多重抑制作用施加在酶上，并表明，没有化合物作为一个绝对的链终止剂。此外，当这些药物位于模板链中时，也发生HIV-1 RT的抑制。这些结果表明，HPMPC和HPMPA通过复杂的机制抑制HIV-1，并表明这类药物具有比以前显示的更广泛的活性谱。
(S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC [cidofovir]) and (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) are potent inhibitors of a variety of DNA viruses. These drugs possess a 3′-hydroxyl equivalent which could support chain extension from an incorporated drug molecule. HPMPC and HPMPA were initially reported to lack activity against human immunodeficiency virus type 1 (HIV-1); more recent results have shown that the octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) esters of HPMPA are potent inhibitors of the virus. We have synthesized the ODE esters of a series of (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] (HPMP) nucleosides, including HPMPC, HPMP-guanine (HPMPG), HPMP-thymine (HPMPT), and HPMP-diaminopurine (HPMPDAP), as well as the ODE ester of the obligate chain terminator (S)-9-[3-methoxy-2-(phosphonomethoxy)-propyl]adenine (MPMPA). All compounds except ODE-HPMPT were inhibitors of HIV-1 replication at low nanomolar concentrations. These compounds were also inhibitors of the replication of HIV-1 variants that are resistant to various nucleoside reverse transcriptase (RT) inhibitors at concentrations several times lower than would be expected to be achievedin vivo. To investigate the mechanism of the antiviral activity, the active metabolites of HPMPC and HPMPA were studied for their effects on reactions catalyzed by HIV-1 RT. Incorporation of HPMPC and HPMPA into a DNA primer strand resulted in multiple inhibitory effects exerted on the enzyme and showed that neither compound acts as an absolute chain terminator. Further, inhibition of HIV-1 RT also occurred when these drugs were located in the template strand. These results indicate that HPMPC and HPMPA inhibit HIV-1 by a complex mechanism and suggest that this class of drugs has a broader spectrum of activity than previously shown.