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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural plasticity of a transmembrane peptide allows self-assembly into biologically active nanoparticles
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Structural plasticity of a transmembrane peptide allows self-assembly into biologically active nanoparticles

机译：跨膜肽的结构可塑性使其能够自组装成具有生物活性的纳米颗粒

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摘要

Significant efforts have been devoted to the development of nanoparticular delivering systems targeting tumors. However, clin ical application of nanoparticles is hampered by insufficient size homogeneity, difficulties in reproducible synthesis and manufac turing, frequent high uptake in the liver, systemic toxicity of the carriers (particularly for inorganic nanoparticles), and insufficient selectivity for tumor cells. We have found that properly modified synthetic analogs of transmembrane domains of membrane pro teins can self-assemble into remarkably uniform spherical nanopar ticles with innate biological activity. Self-assembly is driven by a structural transition of the peptide that adopts predominantly a beta-hairpin conformation in aqueous solutions, but folds into an alpha-helix upon spontaneous fusion of the nanoparticles with cell membrane. A 24-amino acid peptide corresponding to the second transmembrane helix of the CXCR4 forms self-assembled particles that inhibit CXCR4 function in vitro and hamper CXCR4- dependent tumor metastasis in vivo. Furthermore, such nanoparti cles can encapsulate hydrophobic drugs, thus providing a delivery system with the potential for dual biological activity.
机译：已经致力于开发靶向肿瘤的纳米颗粒递送系统。然而，纳米粒子的临床应用受到尺寸均一性不足，难以再现的合成和制造，肝脏中频繁摄取，载体（特别是对于无机纳米粒子）的全身毒性以及对肿瘤细胞的选择性不足的阻碍。我们已经发现，经过适当修饰的膜蛋白跨膜结构域的合成类似物可以自组装成具有先天生物学活性的非常均匀的球形纳米颗粒。自组装由肽的结构转变驱动，该肽主要在水溶液中采用β-发夹构象，但在纳米粒子与细胞膜自发融合时折叠成α-螺旋。对应于CXCR4的第二个跨膜螺旋的24个氨基酸的肽形成自组装的颗粒，该颗粒在体外抑制CXCR4的功能并在体内阻碍CXCR4依赖性肿瘤的转移。此外，这样的纳米颗粒可以包封疏水性药物，因此提供了具有双重生物活性潜力的递送系统。

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  • 作者

    Sergey G. Tarasov; Vadim Gaponenko; O. M. Zack Howard; Yuhong Chen; Joost J. Oppenheim; Marzena A. Dyba; Sriram Subramaniam; Youngshim Lee; Christopher Michejda; Nadya I. Tarasova;

  • 作者单位

    Structural Biophysics Laboratory, National Cancer Institute, P.O. Box B, Frederick, MD 21702-1201;

    Department of Biochemistry and Molecular Genetics,University of Illinois, 900 South Ashland, Chicago, IL 60607;

    Cancer and Inflammation Program, National Cancer Institute, P.O. Box B, Frederick, MD 21702-1201;

    Cancer and Inflammation Program, National Cancer Institute, P.O. Box B, Frederick, MD 21702-1201;

    Cancer and Inflammation Program, National Cancer Institute, P.O. Box B, Frederick, MD 21702-1201;

    Structural Biophysics Laboratory, National Cancer Institute, P.O. Box B, Frederick, MD 21702-1201,SAIC-Frederick, Inc., National Cancer Institute, Frederick, MD 21702;

    Laboratory of Cell Biology, National Cancer Institute, 50 South Drive, Bethesda, MD 20892-8008;

    Department of Biochemistry and Molecular Genetics,University of Illinois, 900 South Ashland, Chicago, IL 60607;

    Structural Biophysics Laboratory, National Cancer Institute, P.O. Box B, Frederick, MD 21702-1201;

    Cancer and Inflammation Program, National Cancer Institute, P.O. Box B, Frederick, MD 21702-1201;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    virus-like particles; cxcl12; cancer; undruggable target;

    机译：病毒样颗粒;cxcl12;癌症;不可治疗的靶标;

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