Abiological Self-Assembly

描述（由申请人提供）：本研究的长期目标是：(1)通过合理设计，利用非生物自组装，开发高效的新方法来制备具有明确形状和大小的复杂纳米级分子；(2)深入了解分子识别现象和自组装过程；(3)开发非生物自组装技术，为新型生物医学应用提供平台。[我们的具体目标是：(a)研究小药物样有机分子的包封和主客体相互作用，以及三种不同的、广泛使用的商业抗癌药物（氟尿嘧啶、环磷酰胺、阿霉素）的包封；(b)研究预先设计的自组装金属包封蛋白和酶；(c)通过自组装金属膜和多肽（和其他）整合素拮抗剂的多价展示，开发靶向药物递送方法。我们将使用非生物的、协调驱动的和我们的“定向键合”方法来实现这些目标。这种方法允许快速、预先设计的、（合理的）自组装具有良好定义的形状和尺寸的纳米级系统，由于金属d轨道的参与，使得金属配体键具有高度的方向性。此外，配位动力学可以通过调节来进行自我修复，从而实现对预期的、预先设计的超结构的热力学控制。自组装是无数生物过程的核心，所有生物，从最简单的到人类，都依赖于它。蛋白质折叠、核酸组装和三级结构、核糖体、磷脂膜和微管都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、更完整地理解复杂的、尚未被充分理解的生物自组装过程。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疾病的改良化学制剂和化学疗法。

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.