Ⅰ型人类免疫缺陷病毒膜融合抑制剂HR212作用机制研究及新型棉酚衍生物抗病毒活性研究
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摘要
获得性免疫缺陷综合症(AIDS)在1981年首次被发现,两年之后得到了第一个HIV分离株,标志着人类与病原体的斗争进入了一个新的时代。从那以后,HIV感染成为世界范围内影响人类健康的重大问题之一。高效的抗逆转录病毒治疗(HAART)的展开,极大地降低了HIV感染者的发病率和死亡率。然而,耐药突变株和药物的毒性极大地限制了当前的治疗手段,这一情况促使人们不断地寻求新的治疗策略。HIV的进入过程成为当前新药研发中最具有吸引力的靶点。HIV进入抑制剂是抗逆转录病毒治疗方案中的一种合理选择,因为它们可以阻止病毒感染新的细胞,从而有可能阻止或者在很大程度上限制病毒的传播。
七肽重复序列重组蛋白HR212是一种人工设计的Ⅰ型人类免疫缺陷病毒(HIV-1)融合抑制剂,它可以通过大肠杆菌系统以较低的成本进行制备。前期的研究工作表明HR212可以有效地抑制不同HIV-1株系对宿主细胞的侵入和复制,而且与T20相比,它的稳定性更好,对蛋白酶消化的耐受性更强。但是HR212具体的作用机制目前尚不清楚。
HIV-1侵入宿主细胞的过程大致可以分为以下三个阶段：(1)病毒包膜糖蛋白gp120与宿主细胞表面受体CD4的结合；(2)gp120与辅助受体CCR5或CXCR5的结合；(3)gp41的构象发生改变,N端七肽重复区(NHR)形成三聚体,紧接着C端七肽重复区(CHR)折叠与NHR三聚体形成六聚体螺旋束结构,病毒与细胞发生膜融合。研究发现HR212对gp120与CD4的相互作用以及gp120与辅助受体的结合均没有影响,但是ELISA,非变性凝胶电泳和圆二色谱实验结果指出HR212可以有效抑制gp41的NHR和CHR形成六螺旋束。而且荧光非变性凝胶电泳的结果进一步阐明HR212可以与gp41的N端肽N36相互作用形成复合物从而达到阻断六螺旋束形成的目的。这些结果表明HR212通过作用于gp41的NHR区域来达到阻断病毒进入的目的。因此,HR212有望可以开发成一种新型有效的HIV-1进入抑制剂。
棉酚是从棉属植物中提取的一种多酚型化合物。为了探索棉酚的抗病毒效果,我们从提高亲水性和降低毒性两个方面采用多种氨基酸,氨基糖以及寡肽对棉酚的结构进行修饰,合成了一系列的新型棉酚衍生物,并通过体外实验筛选其抗HIV-1活性。我们发现把棉酚的甲酰基用部分氨基酸取代后不仅有效的降低了棉酚的细胞毒性,而且可以增强其抗HIV-1活性。进一步研究指出,左旋棉酚的脂肪族氨基酸衍生物具有最好的抗病毒效果和最低的细胞毒性,其选择性指数与棉酚相比提高了100倍左右。接下来我们进一步检测了(-)-棉酚-L-丙氨酸钠希夫碱(50#)对原代病毒感染PBMC的抑制效果,结果显示该化合物具有针对不同基因型HIV-1病毒的广谱的抑制活性。
传统观点认为棉酚及其衍生物主要通过作用于逆转录酶达到抑制HIV-1复制的目的。但我们通过加药时间梯度实验,假病毒抑制实验以及HIV-1介导的细胞融合实验证明(-)-棉酚-L-丙氨酸钠希夫碱(50#)是一种有效的HIV-1进入抑制剂。因此,它可以作为一种新型HIV-1进入抑制剂的先导化合物进一步研究。
Acquired immunodeficiency syndrome (AIDS) was recognized in1981, and the first human immunodeficiency virus (HIV) was isolated2years later, heralding a new era in the fight against pathogenic viruses. Since then, HIV infection has become a major public health problem worldwide. The introduction of highly active antiretroviral therapy (HAART) has markedly decreased mortality and morbidity. However, drug resistance and high toxicity are serious limitations to current treatments that justify the continuation of research efforts for new strategies and interventions. Viral entry currently represents one of the most attractive targets in the search for new drugs to treat HIV infection. HIV entry inhibitors appear to be a rational step forward in ARV therapy, because they prevent the virus from infecting new host cells, and may potentially stop or significantly limit HIV transmission.
HR212, a recombinant protein composed of the heptad repeat, is a rationally designed human immunodeficiency virus type1(HIV-1) fusion inhibitor. This protein can be easily produced by E. coli at a low cost. Previously, studies indicated that HR212can efficiently inhibit the entry and replication of both laboratory and clinical HIV-1strains, and this protein is more stable and less sensitive to proteinases than the T20. However, the potential mechanism of action of HR212is still not clear.
The procedure of HIV-1entry into the host cells can be divided into three main steps:(Ⅰ) attachment of the viral gp120to the CD4T cell receptor,(Ⅱ) binding of the gp120to CCR5or CXCR4co-receptors and (Ⅲ) gp41changes its conformation by forming N-helix trimer between N-heptad repeats (NHRs) and then six-helix bundle between the N-trimer and the C-heptad repeats (CHRs), the viral and cellular membranes fusion. In the present study, we demonstrated that HR212does not block gp120-CD4binding or interfere with the HIV-1coreceptor CXCR4. However, HR212inhibited the fusion-active gp41core formation mimicked by peptides derived from the viral gp41N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), as determined by ELISA, native polyacrylamide gel electrophoresis, and circular dichroism analysis. Moreover, the fluorescence native polyacrylamide gel electrophoresis (FN-PAGE) indicated that HR212could form a complex with peptide N36to block the gp41fusogenic core formation. These results suggest that HR212inhibits HIV-1entry by targeting the NHR region of gp41. Therefore, HR212can be potentially developed as a novel, high-efficiency HIV-1entry inhibitor.
Gossypol is a polyphenolic aldehyde extracted from cotton plants. In order to explore the antiviral effect of gossypol, from the aspects of improving hydrophilicity and lower toxicity, a series of amino acids, amino sugars, and oligopeptides have been used to modify gossypol's structure and a number of novel gossypol derivatives have been synthesized and screened in vitro for their anti-HIV-1activity. We found that replacing the aldehyde groups of gossypol with some amino acids not only reduced the cytotoxicity but also enhanced the activities against HIV-1. Further study indicated that the neutral amino acids with aliphatic group derivatives of (-)-gossypol showed the strongest inhibitory activity and the lowest cytotoxicity in vitro among all the derivatives tested. The selectivity index of the novel (-)-gossypol-neutral amino acid conjugates is increased100fold when compared with gossypol alone. Additionally, the inhibitory activities of the (-)-gossypol bis L-alanine sodium scruff's base (50#) on infection of PBMC by primary HIV-1strains were also determined. This compound had potent inhibitory activity on infection by primary HIV-1strains with distinct genotypes and biotypes. This result suggest that the novel (-)-gossypol derivative has potent antiviral activity against a broad spectrum of HIV-1strains.
It is widely accepted that gossypol and gossypol derivatives inhibit HIV-1replication by targeting reverse transcriptase. However, from the results of our time-of-addition assay, HIV-1-mediated cell fusion assay and pseudotyped virus assay, we demonstrate that the (-)-gossypol bis L-alanine sodium schiff's base (50#) is an effective HIV-1entry inhibitor. Thus it may be used as lead compound of a new type of anti-HIV entry inhibitors for further study.
七肽重复序列重组蛋白HR212是一种人工设计的Ⅰ型人类免疫缺陷病毒(HIV-1)融合抑制剂,它可以通过大肠杆菌系统以较低的成本进行制备。前期的研究工作表明HR212可以有效地抑制不同HIV-1株系对宿主细胞的侵入和复制,而且与T20相比,它的稳定性更好,对蛋白酶消化的耐受性更强。但是HR212具体的作用机制目前尚不清楚。
HIV-1侵入宿主细胞的过程大致可以分为以下三个阶段：(1)病毒包膜糖蛋白gp120与宿主细胞表面受体CD4的结合；(2)gp120与辅助受体CCR5或CXCR5的结合；(3)gp41的构象发生改变,N端七肽重复区(NHR)形成三聚体,紧接着C端七肽重复区(CHR)折叠与NHR三聚体形成六聚体螺旋束结构,病毒与细胞发生膜融合。研究发现HR212对gp120与CD4的相互作用以及gp120与辅助受体的结合均没有影响,但是ELISA,非变性凝胶电泳和圆二色谱实验结果指出HR212可以有效抑制gp41的NHR和CHR形成六螺旋束。而且荧光非变性凝胶电泳的结果进一步阐明HR212可以与gp41的N端肽N36相互作用形成复合物从而达到阻断六螺旋束形成的目的。这些结果表明HR212通过作用于gp41的NHR区域来达到阻断病毒进入的目的。因此,HR212有望可以开发成一种新型有效的HIV-1进入抑制剂。
棉酚是从棉属植物中提取的一种多酚型化合物。为了探索棉酚的抗病毒效果,我们从提高亲水性和降低毒性两个方面采用多种氨基酸,氨基糖以及寡肽对棉酚的结构进行修饰,合成了一系列的新型棉酚衍生物,并通过体外实验筛选其抗HIV-1活性。我们发现把棉酚的甲酰基用部分氨基酸取代后不仅有效的降低了棉酚的细胞毒性,而且可以增强其抗HIV-1活性。进一步研究指出,左旋棉酚的脂肪族氨基酸衍生物具有最好的抗病毒效果和最低的细胞毒性,其选择性指数与棉酚相比提高了100倍左右。接下来我们进一步检测了(-)-棉酚-L-丙氨酸钠希夫碱(50#)对原代病毒感染PBMC的抑制效果,结果显示该化合物具有针对不同基因型HIV-1病毒的广谱的抑制活性。
传统观点认为棉酚及其衍生物主要通过作用于逆转录酶达到抑制HIV-1复制的目的。但我们通过加药时间梯度实验,假病毒抑制实验以及HIV-1介导的细胞融合实验证明(-)-棉酚-L-丙氨酸钠希夫碱(50#)是一种有效的HIV-1进入抑制剂。因此,它可以作为一种新型HIV-1进入抑制剂的先导化合物进一步研究。
Acquired immunodeficiency syndrome (AIDS) was recognized in1981, and the first human immunodeficiency virus (HIV) was isolated2years later, heralding a new era in the fight against pathogenic viruses. Since then, HIV infection has become a major public health problem worldwide. The introduction of highly active antiretroviral therapy (HAART) has markedly decreased mortality and morbidity. However, drug resistance and high toxicity are serious limitations to current treatments that justify the continuation of research efforts for new strategies and interventions. Viral entry currently represents one of the most attractive targets in the search for new drugs to treat HIV infection. HIV entry inhibitors appear to be a rational step forward in ARV therapy, because they prevent the virus from infecting new host cells, and may potentially stop or significantly limit HIV transmission.
HR212, a recombinant protein composed of the heptad repeat, is a rationally designed human immunodeficiency virus type1(HIV-1) fusion inhibitor. This protein can be easily produced by E. coli at a low cost. Previously, studies indicated that HR212can efficiently inhibit the entry and replication of both laboratory and clinical HIV-1strains, and this protein is more stable and less sensitive to proteinases than the T20. However, the potential mechanism of action of HR212is still not clear.
The procedure of HIV-1entry into the host cells can be divided into three main steps:(Ⅰ) attachment of the viral gp120to the CD4T cell receptor,(Ⅱ) binding of the gp120to CCR5or CXCR4co-receptors and (Ⅲ) gp41changes its conformation by forming N-helix trimer between N-heptad repeats (NHRs) and then six-helix bundle between the N-trimer and the C-heptad repeats (CHRs), the viral and cellular membranes fusion. In the present study, we demonstrated that HR212does not block gp120-CD4binding or interfere with the HIV-1coreceptor CXCR4. However, HR212inhibited the fusion-active gp41core formation mimicked by peptides derived from the viral gp41N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), as determined by ELISA, native polyacrylamide gel electrophoresis, and circular dichroism analysis. Moreover, the fluorescence native polyacrylamide gel electrophoresis (FN-PAGE) indicated that HR212could form a complex with peptide N36to block the gp41fusogenic core formation. These results suggest that HR212inhibits HIV-1entry by targeting the NHR region of gp41. Therefore, HR212can be potentially developed as a novel, high-efficiency HIV-1entry inhibitor.
Gossypol is a polyphenolic aldehyde extracted from cotton plants. In order to explore the antiviral effect of gossypol, from the aspects of improving hydrophilicity and lower toxicity, a series of amino acids, amino sugars, and oligopeptides have been used to modify gossypol's structure and a number of novel gossypol derivatives have been synthesized and screened in vitro for their anti-HIV-1activity. We found that replacing the aldehyde groups of gossypol with some amino acids not only reduced the cytotoxicity but also enhanced the activities against HIV-1. Further study indicated that the neutral amino acids with aliphatic group derivatives of (-)-gossypol showed the strongest inhibitory activity and the lowest cytotoxicity in vitro among all the derivatives tested. The selectivity index of the novel (-)-gossypol-neutral amino acid conjugates is increased100fold when compared with gossypol alone. Additionally, the inhibitory activities of the (-)-gossypol bis L-alanine sodium scruff's base (50#) on infection of PBMC by primary HIV-1strains were also determined. This compound had potent inhibitory activity on infection by primary HIV-1strains with distinct genotypes and biotypes. This result suggest that the novel (-)-gossypol derivative has potent antiviral activity against a broad spectrum of HIV-1strains.
It is widely accepted that gossypol and gossypol derivatives inhibit HIV-1replication by targeting reverse transcriptase. However, from the results of our time-of-addition assay, HIV-1-mediated cell fusion assay and pseudotyped virus assay, we demonstrate that the (-)-gossypol bis L-alanine sodium schiff's base (50#) is an effective HIV-1entry inhibitor. Thus it may be used as lead compound of a new type of anti-HIV entry inhibitors for further study.
引文
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