AIM: To address the effect of heat-shock protein 90(HSP90) inhibitors on the release of the hepatitis C virus(HCV), a cell culture-derived HCV(JFH1/HCVcc) from Huh-7 cells was examined.METHODS: We quantified both the ...AIM: To address the effect of heat-shock protein 90(HSP90) inhibitors on the release of the hepatitis C virus(HCV), a cell culture-derived HCV(JFH1/HCVcc) from Huh-7 cells was examined.METHODS: We quantified both the intracellular and extracellular(culture medium) levels of the components(RNA and core) of JFH-1/HCVcc. The intracellular HCV RNA and core levels were determined after the JFH1/HCVcc-infected Huh-7 cells were treated with radicicol for 36 h. The extracellular HCV RNA and core protein levels were determined from the medium of the last 24 h of radicicol treatment. To determine the possible role of the HSP90 inhibitor in HCV release, we examined the effect of a combined application of low doses of the HSP90 inhibitor radicicol and the RNA replication inhibitors cyclosporin A(Cs A) or interferon. Finally, we statistically examined the combined effect of radicicoland Cs A using the combination index(CI) and graphical representation proposed by Chou and Talalay.RESULTS: We found that the HSP90 inhibitors had greater inhibitory effects on the HCV RNA and core protein levels measured in the medium than inside the cells. This inhibitory effect was observed in the presence of a low level of a known RNA replication inhibitor(Cs A or interferon-α). Treating the cells with a combination of radicicol and cyclosporin A for 24 h resulted in significant synergy(CI < 1) that affected the release of both the viral RNA and the core protein. CONCLUSION: In addition to having an inhibitory effect on RNA replication, HSP90 inhibitors may interfere with an HCV replication step that occurs after the synthesis of viral RNA, such as assembly and release.展开更多
Heat shock protein (HSP) is a kind of protein that mainly acts as a molecular chaperone to participate in the synthesis and folding of proteins, maintain the spatial conformation of proteins and protect cells from dam...Heat shock protein (HSP) is a kind of protein that mainly acts as a molecular chaperone to participate in the synthesis and folding of proteins, maintain the spatial conformation of proteins and protect cells from damage and other important biological functions. HSP90 plays an important role in maintaining molecular chaperone structure, regulating cell cycle and apoptosis, coordinating hormone signal transduction and promoting wound healing. And HSP90 also plays an important role in the occurrence and progression of tumors. In recent years, HSP90 inhibitors have made some achievements in molecular targeted therapy for malignant tumors, but further research is needed in clinical application. In this paper, the research status of the relationship between hepatocellular carcinoma targeted by heat shock protein 90 was reviewed.展开更多
Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attent...Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90 N-RJ19 was determined by X-ray diffraction(resolution limit, 2.0 A, PDB code 4 L90). The crystal structure of Hsp90 N-RJ19 was analyzed in detail and compared with that of native Hsp90 N, Hsp90 N-ATP, and Hsp90 N-GDM,respectively. It was indicated that RJ19 interacted with Hsp90~N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90~N to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90~N-RJ 19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90~N provide a rational basis for the design and optimization of novel anticancer drugs.展开更多
The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we s...The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90 Nat the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90~N. The crystal structure and the interaction between Hsp90 Nand FS23 suggest a rational basis for the design of novel antitumor drugs.展开更多
热休克蛋白90(heat shock protein 90,Hsp90)是生物进化过程中高度保守的一类蛋白质,参与很多生理过程,在信号转导中起重要作用。Hsp90抑制剂与Hsp90结合,抑制Hsp90活性,诱导Hsp90作用蛋白降解,从而阻断细胞的增殖生长,是一类具有开发...热休克蛋白90(heat shock protein 90,Hsp90)是生物进化过程中高度保守的一类蛋白质,参与很多生理过程,在信号转导中起重要作用。Hsp90抑制剂与Hsp90结合,抑制Hsp90活性,诱导Hsp90作用蛋白降解,从而阻断细胞的增殖生长,是一类具有开发前景的抗肿瘤、抗病毒药物。现对Hsp90的结构和作用机制以及4类Hsp90抑制剂——格尔德霉素及其衍生物、根赤壳菌素、新生霉素及以嘌呤结构为基础的抑制剂的研究现状进行综述。展开更多
热休克蛋白90(Heat shock protein 90,HSP90)是热休克蛋白家族中在遗传上高度保守的成员之一,HSP90作为一种分子伴侣,主要功能是参与蛋白翻译后的正确折叠加工。近年来研究发现肿瘤细胞中HSP90呈现明显的高表达,并在肺癌的发生发展以及...热休克蛋白90(Heat shock protein 90,HSP90)是热休克蛋白家族中在遗传上高度保守的成员之一,HSP90作为一种分子伴侣,主要功能是参与蛋白翻译后的正确折叠加工。近年来研究发现肿瘤细胞中HSP90呈现明显的高表达,并在肺癌的发生发展以及侵袭转移中都发挥着至关重要的作用。本文就HSP90与肺癌相关性的研究进展以及其抑制剂用于肺癌治疗的研究现状做一综述。展开更多
热休克蛋白90(Heat shock protein 90,HSP90)是热休克蛋白家族中在遗传上高度保守的成员之一,HSP90作为一种分子伴侣,主要功能是参与蛋白翻译后的正确折叠加工。近年来研究发现肿瘤细胞中HSP90呈现明显的高表达,并在肺癌的发生发展以及...热休克蛋白90(Heat shock protein 90,HSP90)是热休克蛋白家族中在遗传上高度保守的成员之一,HSP90作为一种分子伴侣,主要功能是参与蛋白翻译后的正确折叠加工。近年来研究发现肿瘤细胞中HSP90呈现明显的高表达,并在肺癌的发生发展以及侵袭转移中都发挥着至关重要的作用。本文就HSP90与肺癌相关性的研究进展以及其抑制剂用于肺癌治疗的研究现状做一综述。展开更多
肿瘤细胞因癌基因突变、缺氧及营养受限而高度依赖未折叠蛋白反应(unfolded protein response,UPR)。细胞通过内质网(endoplasmic reticulum,ER)膜上3个跨膜蛋白感知未折叠蛋白信号,引起未折叠蛋白反应,动态调控内质网折叠能力,一方面...肿瘤细胞因癌基因突变、缺氧及营养受限而高度依赖未折叠蛋白反应(unfolded protein response,UPR)。细胞通过内质网(endoplasmic reticulum,ER)膜上3个跨膜蛋白感知未折叠蛋白信号,引起未折叠蛋白反应,动态调控内质网折叠能力,一方面通过暂时减缓翻译和加快蛋白质流出减少ER蛋白质折叠负担,另一方面通过转录因子提高伴侣分子合成,增加ER折叠能力。未折叠的蛋白质长时间积聚在ER会对细胞产生毒性,引起不能缓解的ER应激状态,启动细胞凋亡程序。热休克蛋白90(heat shock protein 90,Hsp90)是一种进化保守的伴侣分子,参与了300多种新生蛋白质的折叠与成熟,其中包括UPR重要信号IRE1α(inositol-requiring enzyme 1α)。Hsp90抑制剂导致细胞产生大量未折叠蛋白质,同时直接诱导IRE1α的降解,从而破坏UPR恢复蛋白质平衡的能力,诱导UPR相关凋亡。目前,Hsp90抑制剂可有效诱导分泌型肿瘤细胞如骨髓瘤以及RAS突变肿瘤UPR途径的凋亡。展开更多
文摘AIM: To address the effect of heat-shock protein 90(HSP90) inhibitors on the release of the hepatitis C virus(HCV), a cell culture-derived HCV(JFH1/HCVcc) from Huh-7 cells was examined.METHODS: We quantified both the intracellular and extracellular(culture medium) levels of the components(RNA and core) of JFH-1/HCVcc. The intracellular HCV RNA and core levels were determined after the JFH1/HCVcc-infected Huh-7 cells were treated with radicicol for 36 h. The extracellular HCV RNA and core protein levels were determined from the medium of the last 24 h of radicicol treatment. To determine the possible role of the HSP90 inhibitor in HCV release, we examined the effect of a combined application of low doses of the HSP90 inhibitor radicicol and the RNA replication inhibitors cyclosporin A(Cs A) or interferon. Finally, we statistically examined the combined effect of radicicoland Cs A using the combination index(CI) and graphical representation proposed by Chou and Talalay.RESULTS: We found that the HSP90 inhibitors had greater inhibitory effects on the HCV RNA and core protein levels measured in the medium than inside the cells. This inhibitory effect was observed in the presence of a low level of a known RNA replication inhibitor(Cs A or interferon-α). Treating the cells with a combination of radicicol and cyclosporin A for 24 h resulted in significant synergy(CI < 1) that affected the release of both the viral RNA and the core protein. CONCLUSION: In addition to having an inhibitory effect on RNA replication, HSP90 inhibitors may interfere with an HCV replication step that occurs after the synthesis of viral RNA, such as assembly and release.
文摘Heat shock protein (HSP) is a kind of protein that mainly acts as a molecular chaperone to participate in the synthesis and folding of proteins, maintain the spatial conformation of proteins and protect cells from damage and other important biological functions. HSP90 plays an important role in maintaining molecular chaperone structure, regulating cell cycle and apoptosis, coordinating hormone signal transduction and promoting wound healing. And HSP90 also plays an important role in the occurrence and progression of tumors. In recent years, HSP90 inhibitors have made some achievements in molecular targeted therapy for malignant tumors, but further research is needed in clinical application. In this paper, the research status of the relationship between hepatocellular carcinoma targeted by heat shock protein 90 was reviewed.
基金supported by the National Natural Science Foundation of China(Nos.31401185 and 81402850)the Introduced talents Foundation of Xi'an Medical University(No.2015 RCYJ 01)
文摘Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90 N-RJ19 was determined by X-ray diffraction(resolution limit, 2.0 A, PDB code 4 L90). The crystal structure of Hsp90 N-RJ19 was analyzed in detail and compared with that of native Hsp90 N, Hsp90 N-ATP, and Hsp90 N-GDM,respectively. It was indicated that RJ19 interacted with Hsp90~N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90~N to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90~N-RJ 19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90~N provide a rational basis for the design and optimization of novel anticancer drugs.
基金Supported by National Natural Science Foundation of China(No.81402850)the Natural Science Basic Research Plan in Shaanxi Province of China(No.2015JM3114)+1 种基金the Introduced talents Foundation of Xi’an Medical University(No.2015 RCYJ01)the Doctorate Foundation of Xi’an Medical University(No.2015 DOC23)
文摘The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90 Nat the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90~N. The crystal structure and the interaction between Hsp90 Nand FS23 suggest a rational basis for the design of novel antitumor drugs.
文摘热休克蛋白90(heat shock protein 90,Hsp90)是生物进化过程中高度保守的一类蛋白质,参与很多生理过程,在信号转导中起重要作用。Hsp90抑制剂与Hsp90结合,抑制Hsp90活性,诱导Hsp90作用蛋白降解,从而阻断细胞的增殖生长,是一类具有开发前景的抗肿瘤、抗病毒药物。现对Hsp90的结构和作用机制以及4类Hsp90抑制剂——格尔德霉素及其衍生物、根赤壳菌素、新生霉素及以嘌呤结构为基础的抑制剂的研究现状进行综述。
文摘热休克蛋白90(Heat shock protein 90,HSP90)是热休克蛋白家族中在遗传上高度保守的成员之一,HSP90作为一种分子伴侣,主要功能是参与蛋白翻译后的正确折叠加工。近年来研究发现肿瘤细胞中HSP90呈现明显的高表达,并在肺癌的发生发展以及侵袭转移中都发挥着至关重要的作用。本文就HSP90与肺癌相关性的研究进展以及其抑制剂用于肺癌治疗的研究现状做一综述。
文摘热休克蛋白90(Heat shock protein 90,HSP90)是热休克蛋白家族中在遗传上高度保守的成员之一,HSP90作为一种分子伴侣,主要功能是参与蛋白翻译后的正确折叠加工。近年来研究发现肿瘤细胞中HSP90呈现明显的高表达,并在肺癌的发生发展以及侵袭转移中都发挥着至关重要的作用。本文就HSP90与肺癌相关性的研究进展以及其抑制剂用于肺癌治疗的研究现状做一综述。
文摘肿瘤细胞因癌基因突变、缺氧及营养受限而高度依赖未折叠蛋白反应(unfolded protein response,UPR)。细胞通过内质网(endoplasmic reticulum,ER)膜上3个跨膜蛋白感知未折叠蛋白信号,引起未折叠蛋白反应,动态调控内质网折叠能力,一方面通过暂时减缓翻译和加快蛋白质流出减少ER蛋白质折叠负担,另一方面通过转录因子提高伴侣分子合成,增加ER折叠能力。未折叠的蛋白质长时间积聚在ER会对细胞产生毒性,引起不能缓解的ER应激状态,启动细胞凋亡程序。热休克蛋白90(heat shock protein 90,Hsp90)是一种进化保守的伴侣分子,参与了300多种新生蛋白质的折叠与成熟,其中包括UPR重要信号IRE1α(inositol-requiring enzyme 1α)。Hsp90抑制剂导致细胞产生大量未折叠蛋白质,同时直接诱导IRE1α的降解,从而破坏UPR恢复蛋白质平衡的能力,诱导UPR相关凋亡。目前,Hsp90抑制剂可有效诱导分泌型肿瘤细胞如骨髓瘤以及RAS突变肿瘤UPR途径的凋亡。
