化学小分子和纳米金对自吞噬影响的研究
摘要
自噬是相对保守机制，它通过包裹细胞内受损的细胞器以及错误折叠的蛋白质将其运输到溶酶体中降解以维持细胞的动态平衡。自噬在癌症和神经退行性疾病中有着非常重要的作用。3-MA是应用最为广泛的自吞噬体的抑制剂。但其溶解度非常差，100%抑制自吞噬体的浓度为10mM。3-MA（3-methyladenine）为6-氨基-3-甲基嘌呤，它是由嘧啶和咪唑环并合而成的并环体系。而3-MA N3和C6位是活性官能团，从氨基出发改造最为容易，可以形成多种极性的基团。我们通过在3-MA的N3和C6加入不同的官能团合成出36种3-MA的衍生物。经过高通量筛选发现有3种化学小分子能够抑制自噬。应用免疫荧光进一步验证了20,24和34在浓度为1mM对自吞噬体有非常好的抑制效果，特别是34100%抑制自噬的最低浓度为50μM。并确定这三种化学小分子抑制自吞噬是通过抑制Vps34酶的活性实现的。我们研究表明对3-MA改造是开发自吞噬体抑制剂的最有效的方式，并为临床研究奠定基础。最近研究表明纳米颗粒诱导自吞噬。金颗粒是一种纳米材料，在生物学和医学方面应用的非常广泛。我们通过实验发现，金颗粒通过内吞途径进入细胞，且直径越大进入细胞越多，最终滞留在溶酶体中，并通过改变溶酶体pH值破坏了溶酶体使自吞噬的不能被溶酶体降解，导致细胞中自吞噬体增多。我们的研究为纳米材料在生物学及医学中的应用有着非常重要的指导作用。
Autophagy is a conserved degradation process misfolded or aggregated proteinsand damaged organelles are engulfed by special double membrane vesicles termedautophagosome and subsequencetly delivered to lysosome for degradation and playsimportant pathophysiological roles.3-methyladenine (3-MA) is widely used inautophagic research although a few inhibitors of autophagy are in market. Theefficiency is very low when the concentration is lower than10mM and solubility ispoor in water, which impedes the progress of being widely used in Clinic research.3-MA is6-amino-3-methyl purine, it is blended by the pyrimidine and imidazole ring,pyrimidine and imidazole form the ring system.It can be easily modified at C6and N3poisition. Here we designed and synthesized36derivatives of3-MA. After screeningwith high-throughput system, we identified3small molecues had the inhibitory abilityand further confirmed it by immunoflurorescence staining. We also identified that1mM20,24and34inhibited autophagy, especially34, completely inhibited autophagy in theconcentration of50μM. These new inhibitors of autophagy provide useful tools tostudy the cellular role of the autophagy and may lead to the development of therapeuticagents for the treatment of various diseases.It has been reported that nanoparticles caninduce autophagy. Gold nanoparticle is one of being widely used in biomaterial andbiotechnology. In this paper we found that nanogold entered into NRK cells by thesize-dependent manner. Nano gold caused lysosome alkalinization and blocked thedegradation of autophagosome. So it should be cautious to use nanoparticles fordiseases treatment.
Autophagy is a conserved degradation process misfolded or aggregated proteinsand damaged organelles are engulfed by special double membrane vesicles termedautophagosome and subsequencetly delivered to lysosome for degradation and playsimportant pathophysiological roles.3-methyladenine (3-MA) is widely used inautophagic research although a few inhibitors of autophagy are in market. Theefficiency is very low when the concentration is lower than10mM and solubility ispoor in water, which impedes the progress of being widely used in Clinic research.3-MA is6-amino-3-methyl purine, it is blended by the pyrimidine and imidazole ring,pyrimidine and imidazole form the ring system.It can be easily modified at C6and N3poisition. Here we designed and synthesized36derivatives of3-MA. After screeningwith high-throughput system, we identified3small molecues had the inhibitory abilityand further confirmed it by immunoflurorescence staining. We also identified that1mM20,24and34inhibited autophagy, especially34, completely inhibited autophagy in theconcentration of50μM. These new inhibitors of autophagy provide useful tools tostudy the cellular role of the autophagy and may lead to the development of therapeuticagents for the treatment of various diseases.It has been reported that nanoparticles caninduce autophagy. Gold nanoparticle is one of being widely used in biomaterial andbiotechnology. In this paper we found that nanogold entered into NRK cells by thesize-dependent manner. Nano gold caused lysosome alkalinization and blocked thedegradation of autophagosome. So it should be cautious to use nanoparticles fordiseases treatment.
引文
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