International Research Fellowship Program: Preparation of a Polypeptide-Based Dendrimer Library for the Development and Design of Artificial Enzymes

国际研究奖学金计划使美国科学家和工程师能够在国外进行三到二十四个月的研究。该计划的奖项提供了联合研究的机会，以及使用独特或互补的设施，专业知识和国外的实验条件。鉴于天然系统的复杂性和复杂性，合理的酶设计是一项具有挑战性和艰巨性的任务。目前的技术还没有开发出一种设计氨基酸序列的方法，该氨基酸序列可预测地折叠成所需的构象，从而产生能够具有特定功能的分子。科学家们不得不转向通过定点诱变和活性位点的化学修饰等技术来修饰天然存在的酶框架。为了应对开发大型、复杂的3维酶模拟物的挑战，正在研究新型基于肽的树枝状聚合物库。树枝状聚合物是高度支化的、良好控制的、单分散的大分子，并且提供类似于天然存在的酶的球形形态。它们特有的分支和明确的内部结构提供了一种适合于模仿肽基生物分子的“预折叠”结构。目标结构的制备通过固相肽合成进行。与许多专注于单一目标的方法不同，多样性问题通过组合策略来解决，以产生大量不同的文库成员。一个互补的方法，专注于准备有针对性的图书馆，如催化三联糜蛋白酶- His，Asp，Ser -例如，包括在内。树枝状聚合物和氨基酸重复单元的分支、分级结构的组合开辟了仿生应用的可能性。通过鉴定底物选择性大分子，筛选树状聚合物在传感或“人工鼻”过程中的活性。此外，由氨基酸残基产生的独特纳米环境被评估为催化活性。潜在的醛缩酶，催化碳-碳键形成反应，和酯酶模拟物进行筛选，在荧光测定与染料标记的底物。显然，许多基于肽的树枝状聚合物的探索可能性尚未被发现。

0401973LiangThe International Research Fellowship Program enables U.S. scientists and engineers to conduct three to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-two-month research fellowship by Dr. Catherine O. Liang to work with Dr. Jean-Louis Reymond at University of Berne in Switzerland.In light of the complexity and sophistication of naturally occurring systems, rational enzyme design is a challenging and daunting task. Current technology has not yet developed a way to design an amino acid sequence that folds predictably into a desired conformation resulting in a molecule capable of a specific function. Scientists have had to turn to modification of naturally occurring enzyme frameworks through techniques such as site-directed mutagenesis and chemical modification of the active site. In response to the challenges of developing a large, sophisticated, 3-dimensional enzyme mimic, novel peptide-based dendrimer libraries are being investigated. Dendrimers are highly branched, well-controlled, monodisperse macromolecules and offer a globular morphology similar to naturally occurring enzymes. Their characteristic branching and well-defined interior provides a 'pre-folded' architecture amenable to the mimicry of peptide-based biomolecules. Preparation of target structures is carried out through solid-phase peptide synthesis. Unlike many approaches that focus on a singular target, the issue of diversity is addressed through a combinatorial strategy to generate multitudes of different library members. A complementary approach focusing on the preparation of targeted libraries like the catalytic triad chymotrypsin - His, Asp, Ser - for instance, is included. The combination of the branched, hierarchical structure of dendrimers and amino acid repeat units opens up possibilities towards biomimetic applications. Dendrimers are screened for activity in sensing or "artificial nose" processes through identification of substrate selective macromolecules. In addition, the unique nanoenvironment created by the amino-acid residues is evaluated for catalytic activity. Potential aldolase, which catalyze carbon-carbon bond forming reactions, and esterase mimics are screened in fluorogenic assays with dye-labeled substrates. Clearly many possibilities of exploration into peptide-based dendrimers have yet to be uncovered.