WO2016045115A1 - Hiv-1整合酶抑制剂 - Google Patents

Hiv-1整合酶抑制剂 Download PDF

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WO2016045115A1
WO2016045115A1 PCT/CN2014/087661 CN2014087661W WO2016045115A1 WO 2016045115 A1 WO2016045115 A1 WO 2016045115A1 CN 2014087661 W CN2014087661 W CN 2014087661W WO 2016045115 A1 WO2016045115 A1 WO 2016045115A1
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hiv
sequence
integrase
long terminal
teniposide
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姜凡
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姜凡
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity

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  • the invention relates to a medicament for treating AIDS, in particular to an HIV-1 integrase inhibitor.
  • AIDS acquired immunodeficiency syndrome
  • AIDS also known as AIDS
  • AIDS is a worldwide epidemic. AIDS spreads fast and has a high mortality rate, which is still incurable.
  • HIV Human immunodeficiency virus
  • HIV-1 HIV-1
  • HIV-2 HIV-1 is the main cause of AIDS, and it is also an important direction for the current study of HIV.
  • HAART Highly Active Antiretroviral therapy
  • Integrase is a key enzyme in the life cycle of HIV and is as important as protease and reverse transcriptase. There is no protein structure homologous to HIV integrase in the human body, thus reducing the harm of the enzyme-related drugs.
  • the development of HIV integrase inhibitors, inhibition of viral integration into the human genome, is expected to inhibit or even eliminate the harm of HIV virus to the human body.
  • the development of this target drug has become a hot spot in current world research.
  • HIV integrase inhibitors have been conducted worldwide for more than a decade. However, only MK-0518, an integrase inhibitor, is currently officially approved as a clinical drug. Long-term use of a single drug can easily lead to viral mutations, so there is an urgent need to develop more HIV integrase inhibitors.
  • the HIV-1 integrase inhibitor of the present invention comprises an anchor RNA designed according to a sequence in the U3 region of the HIV-1 long terminal repeat, which is combined with a derivative of podophyllotoxin;
  • a sequence in the U3 region of the HIV-1 long terminal repeat sequence includes any one or more of the following sequences:
  • the anchoring RNA comprises any one or more of the following sequences:
  • sequence 1 of the anchor RNA corresponds to sequence 1 of the HIV-1 long terminal repeat
  • sequence 2 of the anchor RNA corresponds to sequence 2 of the HIV-1 long terminal repeat
  • sequence 3 of the anchor RNA corresponds to HIV-1.
  • Long terminal repeat sequence 3 anchor RNA sequence 4 Sequence 4 corresponding to the HIV-1 long terminal repeat.
  • the HIV-1 integrase inhibitor provided by the embodiment of the present invention firstly discovered two podophyllotoxin biological derivatives - Fanbifu and Teniposide against HIV-1.
  • the inhibition of integrase can make the drug act more accurately between HIV-1 virus and integrase, increase the specificity of drug killing HIV-1 virus, and reduce the damage of drugs to other normal cells.
  • 1 is a schematic view showing the molecular structure of the embodiment of the present invention.
  • FIG. 2 is a schematic view showing the molecular structure of teniposide according to an embodiment of the present invention
  • 3 is a schematic diagram of computer simulation of the molecular docking results of the bifurcation and the 1ZA9-partA part in the embodiment of the present invention
  • FIG. 4 is a schematic diagram of computer simulation of the molecular docking results of the cross-section and the 1ZA9-partB portion in the embodiment of the present invention.
  • 5 is a schematic diagram of computer simulation of the molecular docking results of the cross-section and the 1QS4-partA portion in the embodiment of the present invention.
  • FIG. 6 is a schematic diagram of computer simulation of the molecular docking results of the cross-section and the 1QS4-partB portion in the embodiment of the present invention.
  • FIG. 7 is a schematic diagram of computer simulation of molecular docking results of teniposide and 1ZA9-partA in the embodiment of the present invention.
  • FIG. 8 is a schematic diagram showing computer simulation of molecular docking results of teniposide and 1ZA9-partB in the embodiment of the present invention.
  • FIG. 9 is a schematic diagram showing computer simulation of molecular docking results of teniposide and 1QS4-partA in the embodiment of the present invention.
  • Figure 10 is a schematic diagram showing the computer simulation of the molecular docking results of teniposide and 1QS4-partB in the examples of the present invention.
  • ⁇ 210>1 is a DNA sequence 1 of a sequence in the U3 region of the HIV-1 long terminal repeat
  • ⁇ 210>2 is a DNA sequence 2 of a sequence in the U3 region of the HIV-1 long terminal repeat
  • ⁇ 210>3 is a DNA sequence 3 of a sequence in the U3 region of the HIV-1 long terminal repeat
  • ⁇ 210>4 is a DNA sequence 4 of a sequence in the U3 region of the HIV-1 long terminal repeat
  • ⁇ 210>5 is a DNA sequence 1 anchoring RNA
  • ⁇ 210>6 is a DNA sequence 2 anchoring RNA
  • ⁇ 210>7 is a DNA sequence 3 anchoring RNA
  • ⁇ 210>8 is a DNA sequence 4 anchoring RNA.
  • a preferred embodiment of the HIV-1 integrase inhibitor of the present invention is:
  • a sequence in the U3 region of the HIV-1 long terminal repeat sequence includes any one or more of the following sequences:
  • the anchoring RNA comprises any one or more of the following sequences:
  • sequence 1 of the anchor RNA corresponds to sequence 1 of the HIV-1 long terminal repeat
  • sequence 2 of the anchor RNA corresponds to sequence 2 of the HIV-1 long terminal repeat
  • sequence 3 of the anchor RNA corresponds to HIV-1
  • sequence 4 of the anchor RNA corresponds to sequence 4 of the HIV-1 long terminal repeat.
  • the derivative of podophyllotoxin includes any one or more of dipyridamole and teniposide.
  • Both Bifi and Teniposide can be used to inhibit HIV-1 integrase alone or in combination with anchored RNA to more accurately inhibit HIV-1 integrase.
  • the application of computer molecular docking simulation study of the present invention found that the two clinical drugs, Bifufu and Teniposide, have a good inhibitory effect on HIV-1 integrase. Thereby, the integration of HIV-1 virus into the human genome can be inhibited. It inhibits and even hopes to eliminate the poison of HIV virus to the human body.
  • the present invention designs anchor RNA based on a sequence of HIV-1 long terminal repeats (LTRs).
  • LTRs long terminal repeats
  • the anchored RNA was combined with the bifuran and teniposide, respectively. This allows the drug to act more accurately between the HIV-1 virus and the integrase, increasing the specificity of the drug to kill the HIV-1 virus and reducing the damage of the drug to other normal cells.
  • etoposide phosphate is 4-demethylepipodophyllotoxin 9-[4,6-0-(R)ethylidene coumarin-bD-glucopyranoside],4- (dihydrophosphoric acid);
  • the molecular structure is shown in Figure 1.
  • the molecular structure is shown in Figure 2.
  • the molecular docking results of the partA part of 1ZA9 are: -11.1kcal/mol;
  • the best binding sites for the HIV-1 integrase in the partA portion of 1ZA9 are: amino acid (GLN53) on the I chain, amino acid (GLN146), amino acid on the J chain (GLU246), virus on the S chain. DNA (C25).
  • the molecular docking result of the part B part of 1ZA9 is: -11.0kcal / mol;
  • the best binding sites for the complement and HIV-1 integrase in the partB portion of 1ZA9 are: amino acid on the I chain (GLN146), amino acid (GLN53), viral DNA on the S chain (C25), on the X chain. Viral DNA (T14).
  • the molecular docking result of the partA of the 1QS4 is: -8.3kcal/mol
  • the best binding sites for the HIV-1 integrase in the partA portion of 1QS4 are: amino acid (THR66) on the A chain, amino acid (GLU152), amino acid (LYS156), amino acid (PRO109).
  • the molecular docking result of the partB of the 1QS4 is: -9.3kcal/mol
  • the best binding sites for the complement and HIV-1 integrase in the partB portion of 1QS4 are: amino acid (THR115), amino acid (HIS114), amino acid (SER147), amino acid (TYR143), amino acid (GLN148) in B chain. .
  • the molecular docking result of teniposide and the part A portion of 1ZA9 is: -11.9 kcal / mol;
  • the optimal binding sites for teniposide and HIV-1 integrase in the partA portion of 1ZA9 are: viral DNA on the U chain (G37), viral DNA on the Z chain (G17).
  • the molecular docking of teniposide with the part B portion of 1ZA9 is: -12.9 kcal / mol;
  • the optimal binding region of teniposide to HIV-1 integrase in the partB portion of 1ZA9 is: viral DNA on the U chain (C45), viral DNA on the U chain (T42), viral DNA on the U chain (T43) ), an amino acid on the C chain (VAL250).
  • teniposide can bind to a key site between the integrase and the virus in a model (1ZA9) in which viral DNA is integrated with HIV-1 integrase, thereby interfering with the binding of integrase to viral DNA. Reduce the integration efficiency of integrase and inhibit its function.
  • the molecular docking of teniposide with the part A portion of 1QS4 is: -9.1 kcal / mol;
  • the optimal binding site of teniposide and HIV-1 integrase in the partA portion of 1QS4 is: amino acid on chain A (LYS156), ammonia Acid (GLU152), amino acid (THR66), amino acid (CYS65), amino acid (ARG167).
  • the molecular docking of teniposide with the part B portion of 1QS4 was: -8.7 kcal/mol.
  • the optimal binding sites for teniposide and HIV-1 integrase in the part B portion of 1QS4 are: amino acid (ASN117) on the B chain, amino acid (SER147), amino acid (GLY149), amino acid (PRO145), amino acid (TYR143) ).
  • teniposide can also bind to a key site of integrase and inhibit its function in a model (1QS4) in which HIV-1 integrase does not bind to viral DNA.
  • Anchor RNA was designed based on a sequence of HIV-1 long terminal repeats (LTRs).
  • LTRs long terminal repeats
  • the anchored RNA was combined with the bifuran and teniposide, respectively. This allows the drug to act more accurately between the HIV-1 virus and the integrase, increasing the specificity of the drug to kill the HIV-1 virus and reducing the damage of the drug to other normal cells.

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Abstract

提供了一种HIV-1整合酶抑制剂，包括根据HIV-1长末端重复序列的一段序列设计的锚定RNA，将锚定RNA与鬼臼毒素的衍生物－凡毕复和替尼泊苷相结合。该整合酶抑制剂可以增加药物杀伤HIV-1病毒的特异性，降低药物对其它正常细胞的损伤。

Description

HIV-1整合酶抑制剂 技术领域
本发明涉及一种治疗艾滋病的药物，尤其涉及一种HIV-1整合酶抑制剂。
发明背景
目前，获得性免疫缺陷综合症(acquired immunodeficiency syndrome,简称AIDS)，又称艾滋病，是一种世界范围内的流行病。AIDS传播速度快，死亡率高，目前仍无法治愈。
免疫缺陷病毒(human immunodeficiency virus,简称HIV)，又称艾滋病毒，是引起AIDS的主要原因。HIV分两类，即HIV-1和HIV-2。HIV-1是引起AIDS的主要病原，也是目前研究HIV的重要方向。
将蛋白酶抑制剂和逆转录酶抑制剂进行联合用药，即高效抗逆转录酶疗法(Highly active antiretroviral therapy,HAART)已成为现在发达国家治疗AIDS的标准疗法。HAART疗法需要病人长期服药，费用高昂，且长期用药会促进病毒产生耐药性，并累积药物的毒副作用。
整合酶是HIV生命周期的关键酶，其重要性不亚于蛋白酶和逆转录酶。人体内不存在与HIV整合酶同源的蛋白结构，因此降低了该酶相关药物的危害。开发HIV整合酶抑制剂，抑制病毒整合入人体基因组，有望抑制甚至清除HIV病毒对人体的危害。该靶点药物的开发已成为目前世界研究的热点。
HIV整合酶抑制剂的研究在世界范围内已开展了十余年。然而目前仅有MK-0518一种整合酶抑制剂被正式批准为临床药物。长期使用单一药物，容易导致病毒突变，因此急需开发更多的HIV整合酶抑制剂。
发明内容
本发明的目的是提供一种对HIV-1整合酶很好的抑制效果的HIV-1整合酶抑制剂。
本发明的目的是通过以下技术方案实现的：
本发明的HIV-1整合酶抑制剂，包括根据HIV-1长末端重复序列U3区中的一段序列设计的锚定RNA，将所述锚定RNA与鬼臼毒素的衍生物相结合；
所述HIV-1长末端重复序列U3区中的一段序列包括以下任一种或多种序列：
序列1：5’-GATTGGCAGAACTACACACC-3’；
序列2：5’-TCAGATATCCACTGACCTT-3’；
序列3：5’-GAGTACTTCAAGAACTGCTGACATCGAGC-3’；
序列4：5’-GCGTGGCCTGGGCGGGACTG-3’；
所述锚定RNA包括以下任一种或多种序列：
序列1：5’-GGTGTGTAGTTCTGCCAATC-3’；
序列2：5’-AAGGTCAGTGGATATCTGA-3’；
序列3：5’-GCTCGATGTCAGCAGTTCTTGAAGTACTC-3’；
序列4：5’-CAGTCCCGCCCAGGCCACGC-3’；
上述序列中，锚定RNA的序列1对应HIV-1长末端重复序列的序列1，锚定RNA的序列2对应HIV-1长末端重复序列的序列2，锚定RNA的序列3对应HIV-1长末端重复序列的序列3，锚定RNA的序列4 对应HIV-1长末端重复序列的序列4。
由上述本发明提供的技术方案可以看出，本发明实施例提供的HIV-1整合酶抑制剂，首次发现了两种鬼臼毒素生物衍生物－凡毕复和替尼泊苷对HIV-1整合酶的抑制作用，可以使药物更准确地作用在HIV-1病毒与整合酶之间，增加药物杀伤HIV-1病毒的特异性，降低药物对其它正常细胞的损伤。
附图简要说明
图1为本发明实施例中凡毕复的分子结构示意图；
图2为本发明实施例中替尼泊苷的分子结构示意图；
图3为本发明实施例中凡毕复与1ZA9-partA部分的分子对接结果计算机模拟示意图；
图4为本发明实施例中凡毕复与1ZA9-partB部分的分子对接结果计算机模拟示意图；
图5为本发明实施例中凡毕复与1QS4-partA部分的分子对接结果计算机模拟示意图；
图6为本发明实施例中凡毕复与1QS4-partB部分的分子对接结果计算机模拟示意图；
图7为本发明实施例中替尼泊苷与1ZA9-partA部分的分子对接结果计算机模拟示意图；
图8为本发明实施例中替尼泊苷与1ZA9-partB部分的分子对接结果计算机模拟示意图；
图9为本发明实施例中替尼泊苷与1QS4-partA部分的分子对接结果计算机模拟示意图；
图10为本发明实施例中替尼泊苷与1QS4-partB部分的分子对接结果计算机模拟示意图。
氨基酸或核苷酸序列说明：
<210>1为HIV-1长末端重复序列U3区中的一段序列的DNA序列1；
<210>2为HIV-1长末端重复序列U3区中的一段序列的DNA序列2；
<210>3为HIV-1长末端重复序列U3区中的一段序列的DNA序列3；
<210>4为HIV-1长末端重复序列U3区中的一段序列的DNA序列4；
<210>5为锚定RNA的DNA序列1；
<210>6为锚定RNA的DNA序列2；
<210>7为锚定RNA的DNA序列3；
<210>8为锚定RNA的DNA序列4。
实施本发明的方式
本发明所述的HIV-1整合酶抑制剂，其较佳的具体实施方式是：
包括根据HIV-1长末端重复序列U3区中的一段序列设计的锚定RNA，将所述锚定RNA与鬼臼毒素的衍生物相结合；
所述HIV-1长末端重复序列U3区中的一段序列包括以下任一种或多种序列：
序列1：5’-GATTGGCAGAACTACACACC-3’；
序列2：5’-TCAGATATCCACTGACCTT-3’；
序列3:5’-GAGTACTTCAAGAACTGCTGACATCGAGC-3’；
序列4:5’-GCGTGGCCTGGGCGGGACTG-3’；
所述锚定RNA包括以下任一种或多种序列：
序列1：5’-GGTGTGTAGTTCTGCCAATC-3’；
序列2:5’-AAGGTCAGTGGATATCTGA-3’；
序列3：5’-GCTCGATGTCAGCAGTTCTTGAAGTACTC-3’；
序列4：5’-CAGTCCCGCCCAGGCCACGC-3’；
上述序列中，锚定RNA的序列1对应HIV-1长末端重复序列的序列1，锚定RNA的序列2对应HIV-1长末端重复序列的序列2，锚定RNA的序列3对应HIV-1长末端重复序列的序列3，锚定RNA的序列4对应HIV-1长末端重复序列的序列4。
所述鬼臼毒素的衍生物包括凡毕复和替尼泊苷中的任一种或多种。
凡毕复和替尼泊苷既可以单独使用抑制HIV-1整合酶，也可以分别和锚定RNA结合，更准确地抑制HIV-1整合酶。
八角莲属植物中小八角莲，其地下茎中含有丰富的鬼臼毒素。鬼臼毒素的两种衍生物——凡毕复和替尼泊苷已被成功用于临床治疗各种肿瘤。
本发明应用计算机分子对接模拟研究发现，凡毕复和替尼泊苷这两种临床药物具有对HIV-1整合酶很好的抑制效果。从而可以抑制HIV-1病毒整合入人体基因组。抑制甚至有望清除HIV病毒对人体的毒害。
多年来，这两种药物已被成功应用于临床治疗各种肿瘤。因此，这两种药物在人体的药代动力学情况，及对人体的毒副作用等各项临床研究的数据齐全，且可被稳定的大规模生产。因此，开发该两种药物作为新型HIV-1整合酶抑制剂，具有很好的临床应用和商品化生产的前景。
本发明根据HIV-1长末端重复序列(LTRs)的一段序列设计锚定(anchor)RNA。将锚定RNA分别与凡毕复和替尼泊苷相结合。这样可以使药物更准确地作用在HIV-1病毒与整合酶之间，增加药物杀伤HIV-1病毒的特异性，降低药物对其它正常细胞的损伤。
药物基本信息：
1、药物名称：凡毕复(Etopophos)；药物别名：磷酸依托泊苷(etoposide phosphate)；
分子式成分：磷酸依托泊苷的化学名为4-去甲基差向鬼臼毒素9-[4，6-0-(R)乙叉双香豆素-b-D-吡喃葡萄糖苷]，4-(二氢磷酸)；
分子结构如图1所示。
2、药物中文名：替尼泊苷；药物英文名：Teniposide；药物别名：威猛，VUMON，VM-26；
化学名称：4'-去甲基表鬼臼毒素-BETA-D-噻吩亚甲基吡喃葡萄糖甙；
分子结构如图2所示。
具体实施例：
一、计算机模拟分子对接结果：
1、凡毕复计算机模拟分子对接结果：
(1)将HIV-1整合酶与HIV-1病毒结合后的X-ray衍射模型：1ZA9，分为前后两部分：即partA 和partB。
如图3所示，凡毕复与1ZA9的partA部分的分子对接结果为：-11.1kcal/mol；
凡毕复与HIV-1整合酶在1ZA9的partA部分中最佳结合位点为：I链上的氨基酸(GLN53)，氨基酸(GLN146)，J链上的氨基酸(GLU246)，S链上的病毒DNA(C25)。
如图4所示，凡毕复与1ZA9的partB部分的分子对接结果为：-11.0kcal/mol；
凡毕复与HIV-1整合酶在1ZA9的partB部分中最佳结合位点为：I链上的氨基酸(GLN146)，氨基酸(GLN53)，S链上的病毒DNA(C25)，X链上的病毒DNA(T14)。
由以上结果可见：凡毕复在与HIV-1整合酶结合了病毒DNA的模型(1ZA9)中可以结合在整合酶与病毒之间的关键位点，从而干扰整合酶与病毒DNA的结合，降低整合酶的整合效率，抑制其功能。
(2)将HIV-1整合酶与HIV-1病毒未结合后的X-ray衍射模型：1QS4，分为前后两部分：即partA和partB。
如图5所示，凡毕复与1QS4的partA部分的分子对接结果为：-8.3kcal/mol；
凡毕复与HIV-1整合酶在1QS4的partA部分中最佳结合位点为：A链上的氨基酸(THR66)，氨基酸(GLU152)，氨基酸(LYS156)，氨基酸(PRO109)。
如图6所示，凡毕复与1QS4的partB部分的分子对接结果为：-9.3kcal/mol；
凡毕复与HIV-1整合酶在1QS4的partB部分中最佳结合位点为：B链上的氨基酸(THR115)，氨基酸(HIS114)，氨基酸(SER147)，氨基酸(TYR143)，氨基酸(GLN148)。
由以上结果可见：凡毕复在与HIV-1整合酶未结合病毒DNA的模型(1QS4)中也可以结合在整合酶的关键位点，抑制其功能。
2、替尼泊苷的计算机模拟分子对接结果：
(1)将HIV-1整合酶与HIV-1病毒结合后的X-ray衍射模型：1ZA9，分为前后两部分：即partA和partB。
如图7所示，替尼泊苷与1ZA9的partA部分的分子对接结果为：-11.9kcal/mol；
替尼泊苷与HIV-1整合酶在1ZA9的partA部分中最佳结合位点为：U链上的病毒DNA(G37)，Z链上的病毒DNA(G17)。
如图8所示，替尼泊苷与1ZA9的partB部分的分子对接结果为：-12.9kcal/mol；
替尼泊苷与HIV-1整合酶在1ZA9的partB部分中最佳结合区域为：U链上的病毒DNA(C45)，U链上的病毒DNA(T42)，U链上的病毒DNA(T43)，C链上的氨基酸(VAL250)。
由以上结果可见：替尼泊苷在与HIV-1整合酶结合了病毒DNA的模型(1ZA9)中可以结合在整合酶与病毒之间的关键位点，从而干扰整合酶与病毒DNA的结合，降低整合酶的整合效率，抑制其功能。
(2)将HIV-1整合酶与HIV-1病毒未结合后的X-ray衍射模型：1QS4，分为前后两部分：即partA和partB。
如图9所示，替尼泊苷与1QS4的partA部分的分子对接结果为；-9.1kcal/mol；
替尼泊苷与HIV-1整合酶在1QS4的partA部分中最佳结合位点为：A链上的氨基酸(LYS156)，氨 基酸(GLU152)，氨基酸(THR66)，氨基酸(CYS65)，氨基酸(ARG167)。
如图10所示，替尼泊苷与1QS4的partB部分的分子对接结果为：-8.7kcal/mol。
替尼泊苷与HIV-1整合酶在1QS4的partB部分中最佳结合位点为：B链上的氨基酸(ASN117)，氨基酸(SER147)，氨基酸(GLY149)，氨基酸(PRO145)，氨基酸(TYR143)。
由以上结果可见：替尼泊苷在与HIV-1整合酶未结合病毒DNA的模型(1QS4)中也可以结合在整合酶的关键位点，抑制其功能。
二、利用锚定(anchor)RNA将药物送到HIV-1特定位点上：
根据HIV-1长末端重复序列(LTRs)的一段序列设计锚定(anchor)RNA。将锚定RNA分别与凡毕复和替尼泊苷相结合。这样可以使药物更准确地作用在HIV-1病毒与整合酶之间，增加药物杀伤HIV-1病毒的特异性，降低药物对其它正常细胞的损伤。
氨基酸或核苷酸序列
<210>1
GATTGGCAGAACTACACACC
<210>2
TCAGATATCCACTGACCTT
<210>3
GAGTACTTCAAGAACTGCTGACATCGAGC
<210>4
GCGTGGCCTGGGCGGGACTG
<210>5
GGTGTGTAGTTCTGCCAATC
<210>6
AAGGTCAGTGGATATCTGA
<210>7
GCTCGATGTCAGCAGTTCTTGAAGTACTC
<210>8
CAGTCCCGCCCAGGCCACGC
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明披露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书的保护范围为准。

Claims (2)

  1. 一种HIV-1整合酶抑制剂，其特征在于，包括根据HIV-1长末端重复序列U3区中的一段序列设计的锚定RNA，将所述锚定RNA与鬼臼毒素的衍生物相结合；
    所述HIV-1长末端重复序列U3区中的一段序列包括以下任一种或多种序列：
    序列1：5’-GATTGGCAGAACTACACACC-3’；
    序列2：5’-TCAGATATCCACTGACCTT-3’；
    序列3:5’-GAGTACTTCAAGAACTGCTGACATCGAGC-3’；
    序列4:5’-GCGTGGCCTGGGCGGGACTG-3’；
    所述锚定RNA包括以下任一种或多种序列：
    序列1：5’-GGTGTGTAGTTCTGCCAATC-3’；
    序列2:5’-AAGGTCAGTGGATATCTGA-3’；
    序列3：5’-GCTCGATGTCAGCAGTTCTTGAAGTACTC-3’；
    序列4：5’-CAGTCCCGCCCAGGCCACGC-3’；
    上述序列中，锚定RNA的序列1对应HIV-1长末端重复序列的序列1，锚定RNA的序列2对应HIV-1长末端重复序列的序列2，锚定RNA的序列3对应HIV-1长末端重复序列的序列3，锚定RNA的序列4对应HIV-1长末端重复序列的序列4。
  2. 根据权利要求1所述的HIV-1整合酶抑制剂，其特征在于，所述鬼臼毒素的衍生物包括凡毕复和替尼泊苷中的任一种或多种。
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