Abiological Self-Assembly

描述（由申请人提供）：本研究的广泛长期目标是：（1）通过合理设计，使用非生物自组装，开发用于制备具有明确形状和尺寸的复杂纳米级分子的有效新方法;（2）提供见解并更好地理解分子识别现象和自组装过程;（3）发展非生物自组装技术作为新的生物医学应用平台。[Our具体目标是：（a）研究类药物有机小分子的包封和主客体相互作用，以及三种广泛使用的市售癌症药物的包封情况（氟尿嘧啶、环磷酰胺、阿霉素）;（B）研究通过预先设计的自组装金属笼包封蛋白质和酶;（c）开发通过自组装金属笼和肽（和其他）整联蛋白拮抗剂的多价展示的靶向药物递送方法。我们将使用非生物的，协调驱动的和我们的“定向结合”的方法来实现这些目标。该方法允许具有明确定义的形状和尺寸的纳米级系统的快速、预先设计的（合理的）自组装，这是由于金属d轨道的参与，其允许配价金属-配体键是高度定向的。此外，可以调节配位动力学以进行自我修复，从而实现对所需的、预先设计的超级结构的热力学控制。自我组装是无数生物过程的核心，从最简单的生物到人类，所有生物都依赖于它。蛋白质折叠、核酸组装和三级结构、核糖体、磷脂膜和微管只是自组装的代表性例子。从拟议的非生物自组装研究中获得的见解将适用于更好和更完整地了解复杂的，不太清楚的生物自组装过程。如果这一应用的目标得以实现，生物医学研究人员将拥有新的工具和全新的方法来形成具有独特性质的大型纳米级复杂分子，这些分子将补充和增强经典的共价合成方法。因此，从长远来看，这些方法将有助于发现和生产用于治疗和可能预防医学疾病的改进的化学试剂和化学疗法。 公共卫生相关性：如果这一应用的目标得以实现，生物医学研究人员将拥有新的工具和全新的方法来形成具有独特性质的大型纳米级复杂分子，这些分子将补充和增强经典的共价合成方法。因此，从长远来看，这些方法将有助于发现和生产用于治疗和可能预防医学疾病的改进的化学试剂和化学疗法，特别是。此外，在未来，创新的转染系统和可能的基因调控可能会从这些发现中发展出来。

DESCRIPTION (provided by applicant): The broad long term objectives of this research are: (1) to develop efficient, new methods for the preparation of complex nanoscale molecules with well-defined shapes and sizes, by rational design, using abiological self- assembly; (2) to provide insights and gain a better understanding of molecular recognition phenomena and self-assembly processes; (3) to develop abiological self-assembly as a platform for novel biomedical applications. [Our specific goals are to: (a) examine encapsulation and host-guest interactions of small drug- like organic molecules, as well as the encapsulation of three diverse, widely-used commercially-available cancer drugs (fluorouracil, cyclophosphamide, doxorubicin); (b) study protein and enzyme encapsulation by pre-designed self-assembled metallacages; (c) develop targeted drug delivery methodologies via self- assembled metallacages and the multivalent display of peptidic (and other) integrin antagonists.] We will use abiological, coordination-driven and our "directional bonding" approach to achieve these aims. This methodology allows for the rapid, pre-designed, (rational) self-assembly of nanoscale systems with well- defined shapes and sizes, due to metal d-orbital involvement that allows dative, metal-ligand bonds to be highly directional. Moreover, coordination kinetics can be modulated to engage in self-repair to achieve thermodynamic control of the desired, pre-designed super structures. Self-assembly is at the heart of countless biological processes that all living organisms, from the simplest to humans, depend upon. Protein folding, nucleic acid assembly and tertiary structures, ribosomes, phospholipid membranes and microtubules are but representative examples of self-assembly. Insights gained from the proposed abiological self-assembly studies will be applicable to a better and more complete understanding of the complex, not well-understood biological self-assembly processes. If the aims of this application are achieved, biomedical researchers will have new tools and entirely new approaches for the formation of large, nanoscale, complex molecules with unique properties that will complement and enhance classical covalent synthetic methods. As a consequence, in the long term, these approaches will facilitate the discovery and production of improved chemical agents and chemotherapy for the treatment and possible prevention of medical disorders. PUBLIC HEALTH RELEVANCE: If the aims of this application are achieved, biomedical researchers will have new tools and entirely new approaches for the formation of large, nanoscale, complex molecules with unique properties that will complement and enhance classical covalent synthetic methods. As a consequence, in the long term, these approaches will facilitate the discovery and production of improved chemical agents and chemotherapy for the treatment and possible prevention of medical disorders and in particular. Additionally, in the future, innovative transfection systems and possible gene-regulation may evolve from these discoveries.