靶向toll样受体2多肽的筛选、鉴定及应用
摘要
TLR2(Toll like receptor2)作为固有免疫受体家族的重要成员,参与机体免疫系统抵御体内及体外危险因素的攻击。近期研究表明TLR2还参与包括癌症、自身免疫及心脑血管等多种疾病的发生和进展。本研究发现TLR2在急性粒细胞性白血病细胞高表达。因此靶向TLR2进行药物开发对多种疾病具有很好的治疗前景。本研究主要通过构建TLR2特异性配基细胞筛选模型,从噬菌体展示肽库中筛选出与TLR2特异性结合的多肽。以多肽为载体偶联不同治疗性物质,靶向治疗急性粒细胞白血病和肿瘤。具体内容主要分为以下三部分：
1.TLR2特异性配基细胞筛选模型的构建、验证及TLR2配基多肽的筛选。
为了构建TLR2特异性配基细胞筛选模型,我们将TLR2及其辅助型受体CD14、 TLR1和TLR6的表达质粒与TLR2信号通路NF-κB启动子荧光素酶报告基因质粒共转染至人胚肾HEK293细胞,经过筛选得到稳定表达细胞株。利用这一筛选系统从噬菌体展示7肽库中通过生物淘洗-快速差异筛选配基方法(BRASIL)筛选出与TLR2特异性结合的肽段Pep2和C8,经ELISA、流式细胞术和细胞免疫荧光方法鉴定以上肽段均能特异性结合TLR2。通过荧光素酶活性实验验证肽段C8作为TLR2配基激活TLR2/TLR1信号通路；激光共聚焦实验验证肽段Pep2作为靶向TLR2的细胞穿膜肽经受体内化进入细胞。综上所述,通过以上实验证明我们成功构建了TLR2特异性配基的细胞筛选模型,并且筛选到靶向结合TLR2的多肽。
2.以靶向TLR2细胞穿膜肽Pep2为载体治疗急性粒细胞性白血病和淋巴瘤
细胞穿膜肽作为新的靶向药物传输载体在多种癌症治疗中具有高效低毒的优点。本研究发现TLR2在急性粒细胞性白血病(AML)和多种淋巴瘤细胞中高表达。为了验证靶向结合TLR2的细胞穿膜肽Pep2是否可以作为新的药物传输载体用于治疗AML,我们将该肽段偶联上一段促进细胞凋亡的多肽D(KLAKLAK)2,组成新的嵌合肽Pep2-D(KLAKLAK)2。实验结果表明Pep2-D(KLAKLAK)2可以靶向促进高表达TLR2(TLR2high)的AML细胞发生凋亡,而对低表达TLR2(TLR2low)的慢性粒细胞性白血病(CML)细胞则没有作用。Pep2-D(KLAKLAK)2抗白血病效应进一步在白血病临床骨髓样本和小鼠模型中得到验证。白血病小鼠骨髓切片TUNEL染色表明此嵌合多肽以TLR2依赖性方式促进AML细胞凋亡。综上所述,本研究证明TLR2可以作为治疗AML和淋巴瘤的潜在靶点,而嵌合多肽Pep2-D(KLAKLAK)2是一个有开发价值的候选药物。
3.以细胞穿膜肽Pep2为载体靶向抑制TRB3的功能抑制肿瘤发生与进展
肿瘤细胞的过度增殖、侵袭和转移涉及一系列相关基因的表达和功能异常。TRB3(Tribbles Homologue3)在多种肿瘤细胞及肿瘤组织中高表达。为了探究TRB3与肿瘤发生和进展的关系,本研究发现抑制肿瘤细胞内TRB3的高表达能抑制肿瘤细胞的自噬活性。本研究深入探讨了TRB3调节自噬的分子机制,发现TRB3主要与自噬通路的“货车蛋白"P62相互作用,进而干扰P62与泛素化蛋白以及自噬标志蛋白LC3的结合,造成自噬活性被抑制,从而促进肿瘤的发生和进展。本研究进一步发现干扰肿瘤细胞内TRB3的表达显著降低肿瘤细胞的增殖、侵袭及转移能力,提高荷瘤动物生存率。这些结果提示TRB3是治疗肿瘤的一个潜在靶点。利用这一机制,本研究从P62蛋白结构域中筛选出一段靶向结合TRB3的具有α螺旋结构的肽段,以细胞穿膜肽Pep2作为载体将其带入肿瘤细胞。结果显示该嵌合肽能干扰TRB3与P62的结合,激活肿瘤细胞自噬活性,在体内和体外起到抑制肿瘤生长和转移的作用。综上所述,我们的研究证明TRB3能作为连接自噬和肿瘤的桥梁,靶向阻断P62/TRB3之间相互作用可以明显抑制肿瘤发展。
Toll-like receptor2plays a fundamental role in pathogen recognition and activation of innate immunity as a pattern recognition receptor. Recent studies found that TLR2activity participated with the pathogenesis of autoimmune diseases, tumor carcinogenesis and cardio-cerebrovascular diseases. In this study, enhanced expression of toll like receptor2(TLR2) was observed in acute myeloid leukemia (AML) cells. Therefore, TLR2and its signalling components are promising target candidates for drug development. Our study established a TLR2receptor-based cell screening model and new TLR2agonist and cell penetrating peptide were identified from the Ph.D.TM-7Phage Display Peptide Library. Chimeric peptides composed of the TLR2-binding motif linked to therapeutic effect sequences target acute myeloid leukemia or tumors. The major research results are shown as following:
1. Establishment, identification and application of TLR2receptor-based cell screening model.
To establish a TLR2receptor-based cell screening model, human TLR2and co-receptors CD14, TLR1and TLR6plasmids and NF-κB promoter-driven luciferase reporter plasmids were co-transfected into Human Embryonic Kidney cells (HEK293). Single clones were then isolated and characterized. Using this screening system, human TLR2-binding peptide C8and Pep2were obtained from the Ph.D.TM-7Phage Display Peptide Library. The binding characteristic of C8and Pep2with human TLR2was evaluated by ELISA, flow cytometry and immunofluorescence. The NF-κB luciferase activity assay showed that C8could activate the TLR2/TLR1signaling pathway. The immunefluorence assay revealed that Pep2could penetrate into TLR2expressing cells. In conclusion, we have successfully established the TLR2receptor-based cell screening system and new TLR2-binding peptides were identified through this system.
2. Targeting leukemia and lymphoma with a proapoptotic peptide conjugated to a toll-like receptor2-mediated cell-penetrating peptide.
Cell-penetrating peptides provide a unique platform to create a new generation of cancer therapeutics with enhanced efficacy and diminished toxicity. In this study, enhanced expression of toll like receptor2(TLR2) was observed in acute myeloid leukemia (AML) cells. Screening of a phage display peptide library using Bio-panning and Rapid Analysis of Selective Interactive Ligands (BRASIL) identified a TLR2-binding cell penetrating peptide motif, Pep2. We show that Pep2targeted and penetrated into leukemia cells in a TLR2-dependent manner. Moreover, a synthetic, chimeric peptide composed of the TLR2-binding motif linked to a programmed cell death-inducing sequence, D(KLAKLAK)2, induced apoptosis in AML cells with high TLR2expression (TLR2high) but not in chronic myeloid leukemia (CML) cells with low TLR2expression (TLR2low). The anti-leukemia activity of this chimeric peptide was confirmed in leukemia patient samples and an animal model of myeloid leukemia, as the development of leukemia was significantly delayed in mice with TLR2high AML compared to TLR2low CML NOD/SCID mice. TUNEL assays on bone marrow tissue slices revealed that the chimerical peptide induced leukemia cell apoptosis in a TLR2-dependent manner. Together, our findings indicate that TLR2is a potential therapeutic target for the prevention and treatment of AML, and the prototype, Pep2-D(KLAKLAK)2, is a promising drug candidate in this setting.
3. TRB3connects autophagy to tumorigenesis and progression.
Cancer initiation and progression are associated with autophogy with unclear mechanism. Here we report that silencing of TRB3not only restored suppressed autophagic flux and promoted autophagy-associated cells death, but also attenuated tumor growth and metastasis. However, isotopic expression of TRB3enhanced the susceptibility to tumor development. Notably, TRB3physically interacted with p62to interfere with binding of p62to LC3and ubiquitinated proteins, resulting in an inhibition of autophagy-dependent ubiquitination degradation and accumulation of cancer-promoting factors. Treatment of animals with peptides corresponding to α-helix peptide of p62binding to TRB3attenuated tumor growth and metastasis. Our results demonstrate that TRB3connects autophogy to cancer development and progression. Targeting the TRB3/p62interaction is a therapeutic strategy against cancer progression.
1.TLR2特异性配基细胞筛选模型的构建、验证及TLR2配基多肽的筛选。
为了构建TLR2特异性配基细胞筛选模型,我们将TLR2及其辅助型受体CD14、 TLR1和TLR6的表达质粒与TLR2信号通路NF-κB启动子荧光素酶报告基因质粒共转染至人胚肾HEK293细胞,经过筛选得到稳定表达细胞株。利用这一筛选系统从噬菌体展示7肽库中通过生物淘洗-快速差异筛选配基方法(BRASIL)筛选出与TLR2特异性结合的肽段Pep2和C8,经ELISA、流式细胞术和细胞免疫荧光方法鉴定以上肽段均能特异性结合TLR2。通过荧光素酶活性实验验证肽段C8作为TLR2配基激活TLR2/TLR1信号通路；激光共聚焦实验验证肽段Pep2作为靶向TLR2的细胞穿膜肽经受体内化进入细胞。综上所述,通过以上实验证明我们成功构建了TLR2特异性配基的细胞筛选模型,并且筛选到靶向结合TLR2的多肽。
2.以靶向TLR2细胞穿膜肽Pep2为载体治疗急性粒细胞性白血病和淋巴瘤
细胞穿膜肽作为新的靶向药物传输载体在多种癌症治疗中具有高效低毒的优点。本研究发现TLR2在急性粒细胞性白血病(AML)和多种淋巴瘤细胞中高表达。为了验证靶向结合TLR2的细胞穿膜肽Pep2是否可以作为新的药物传输载体用于治疗AML,我们将该肽段偶联上一段促进细胞凋亡的多肽D(KLAKLAK)2,组成新的嵌合肽Pep2-D(KLAKLAK)2。实验结果表明Pep2-D(KLAKLAK)2可以靶向促进高表达TLR2(TLR2high)的AML细胞发生凋亡,而对低表达TLR2(TLR2low)的慢性粒细胞性白血病(CML)细胞则没有作用。Pep2-D(KLAKLAK)2抗白血病效应进一步在白血病临床骨髓样本和小鼠模型中得到验证。白血病小鼠骨髓切片TUNEL染色表明此嵌合多肽以TLR2依赖性方式促进AML细胞凋亡。综上所述,本研究证明TLR2可以作为治疗AML和淋巴瘤的潜在靶点,而嵌合多肽Pep2-D(KLAKLAK)2是一个有开发价值的候选药物。
3.以细胞穿膜肽Pep2为载体靶向抑制TRB3的功能抑制肿瘤发生与进展
肿瘤细胞的过度增殖、侵袭和转移涉及一系列相关基因的表达和功能异常。TRB3(Tribbles Homologue3)在多种肿瘤细胞及肿瘤组织中高表达。为了探究TRB3与肿瘤发生和进展的关系,本研究发现抑制肿瘤细胞内TRB3的高表达能抑制肿瘤细胞的自噬活性。本研究深入探讨了TRB3调节自噬的分子机制,发现TRB3主要与自噬通路的“货车蛋白"P62相互作用,进而干扰P62与泛素化蛋白以及自噬标志蛋白LC3的结合,造成自噬活性被抑制,从而促进肿瘤的发生和进展。本研究进一步发现干扰肿瘤细胞内TRB3的表达显著降低肿瘤细胞的增殖、侵袭及转移能力,提高荷瘤动物生存率。这些结果提示TRB3是治疗肿瘤的一个潜在靶点。利用这一机制,本研究从P62蛋白结构域中筛选出一段靶向结合TRB3的具有α螺旋结构的肽段,以细胞穿膜肽Pep2作为载体将其带入肿瘤细胞。结果显示该嵌合肽能干扰TRB3与P62的结合,激活肿瘤细胞自噬活性,在体内和体外起到抑制肿瘤生长和转移的作用。综上所述,我们的研究证明TRB3能作为连接自噬和肿瘤的桥梁,靶向阻断P62/TRB3之间相互作用可以明显抑制肿瘤发展。
Toll-like receptor2plays a fundamental role in pathogen recognition and activation of innate immunity as a pattern recognition receptor. Recent studies found that TLR2activity participated with the pathogenesis of autoimmune diseases, tumor carcinogenesis and cardio-cerebrovascular diseases. In this study, enhanced expression of toll like receptor2(TLR2) was observed in acute myeloid leukemia (AML) cells. Therefore, TLR2and its signalling components are promising target candidates for drug development. Our study established a TLR2receptor-based cell screening model and new TLR2agonist and cell penetrating peptide were identified from the Ph.D.TM-7Phage Display Peptide Library. Chimeric peptides composed of the TLR2-binding motif linked to therapeutic effect sequences target acute myeloid leukemia or tumors. The major research results are shown as following:
1. Establishment, identification and application of TLR2receptor-based cell screening model.
To establish a TLR2receptor-based cell screening model, human TLR2and co-receptors CD14, TLR1and TLR6plasmids and NF-κB promoter-driven luciferase reporter plasmids were co-transfected into Human Embryonic Kidney cells (HEK293). Single clones were then isolated and characterized. Using this screening system, human TLR2-binding peptide C8and Pep2were obtained from the Ph.D.TM-7Phage Display Peptide Library. The binding characteristic of C8and Pep2with human TLR2was evaluated by ELISA, flow cytometry and immunofluorescence. The NF-κB luciferase activity assay showed that C8could activate the TLR2/TLR1signaling pathway. The immunefluorence assay revealed that Pep2could penetrate into TLR2expressing cells. In conclusion, we have successfully established the TLR2receptor-based cell screening system and new TLR2-binding peptides were identified through this system.
2. Targeting leukemia and lymphoma with a proapoptotic peptide conjugated to a toll-like receptor2-mediated cell-penetrating peptide.
Cell-penetrating peptides provide a unique platform to create a new generation of cancer therapeutics with enhanced efficacy and diminished toxicity. In this study, enhanced expression of toll like receptor2(TLR2) was observed in acute myeloid leukemia (AML) cells. Screening of a phage display peptide library using Bio-panning and Rapid Analysis of Selective Interactive Ligands (BRASIL) identified a TLR2-binding cell penetrating peptide motif, Pep2. We show that Pep2targeted and penetrated into leukemia cells in a TLR2-dependent manner. Moreover, a synthetic, chimeric peptide composed of the TLR2-binding motif linked to a programmed cell death-inducing sequence, D(KLAKLAK)2, induced apoptosis in AML cells with high TLR2expression (TLR2high) but not in chronic myeloid leukemia (CML) cells with low TLR2expression (TLR2low). The anti-leukemia activity of this chimeric peptide was confirmed in leukemia patient samples and an animal model of myeloid leukemia, as the development of leukemia was significantly delayed in mice with TLR2high AML compared to TLR2low CML NOD/SCID mice. TUNEL assays on bone marrow tissue slices revealed that the chimerical peptide induced leukemia cell apoptosis in a TLR2-dependent manner. Together, our findings indicate that TLR2is a potential therapeutic target for the prevention and treatment of AML, and the prototype, Pep2-D(KLAKLAK)2, is a promising drug candidate in this setting.
3. TRB3connects autophagy to tumorigenesis and progression.
Cancer initiation and progression are associated with autophogy with unclear mechanism. Here we report that silencing of TRB3not only restored suppressed autophagic flux and promoted autophagy-associated cells death, but also attenuated tumor growth and metastasis. However, isotopic expression of TRB3enhanced the susceptibility to tumor development. Notably, TRB3physically interacted with p62to interfere with binding of p62to LC3and ubiquitinated proteins, resulting in an inhibition of autophagy-dependent ubiquitination degradation and accumulation of cancer-promoting factors. Treatment of animals with peptides corresponding to α-helix peptide of p62binding to TRB3attenuated tumor growth and metastasis. Our results demonstrate that TRB3connects autophogy to cancer development and progression. Targeting the TRB3/p62interaction is a therapeutic strategy against cancer progression.
引文
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