Phage Display of Multicyclic Peptides

在化学系生命过程化学（CLP）项目的支持下，波士顿学院的高健民教授正在开发多环肽库，以促进发现针对病原菌蛋白质的抑制剂。多环肽是氨基酸的短聚合物，其中主链和侧链交联以形成复杂的闭合环状结构。天然存在形式的多环肽，如万古霉素，已成为抗菌药物的丰富来源。然而，难以开发具有所需生物活性的合成多环肽。Gao团队将整合分子生物学和合成化学，构建具有复杂多环结构的肽库。这些合成的多环肽将使用噬菌体展示筛选其抑制细菌蛋白的能力，噬菌体展示是一种允许鉴定显示特定所需生物活性的化合物的技术。这个跨学科项目将通过让学生参与研究来帮助培养下一代科学家，包括本科生和高中实习生。噬菌体展示技术是一种流行的肽库筛选技术，但目前主要局限于展示线性或简单的二硫键环化肽。这些肽与肽天然产物相比在结构复杂性方面有所不足，肽天然产物通常显示多环结构。在这项研究中，Gao小组的目标是开发新的化学策略，在噬菌体表面构建多环肽库。这些策略包括开发和检查各种蛋白质缀合化学，以组合使用来实现噬菌体展示肽的顺序多环化。具体而言，该研究将利用新开发的超快半胱氨酸缀合化学，以高效率和位点选择性交联特定的氨基酸残基。这些新的多环肽库将用于筛选和选择特定细菌蛋白质-蛋白质相互作用的抑制剂。如果成功，该项目将提供一个强大的和广泛适用的策略，抑制蛋白质-蛋白质相互作用，如那些促进免疫反应逃避的细菌pathogen.This奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

With the support of the Chemistry of Life Processes (CLP) program in the Chemistry Division, Professor Jianmin Gao from Boston College is developing multicyclic peptide libraries to facilitate the discovery of inhibitors against proteins of pathogenic bacteria. Multicyclic peptides are short polymers of amino acids in which the backbones and side chains crosslink to form complex closed circular structures. Naturally occurring forms of multicyclic peptides, such as vancomycin, have been rich sources of antibacterial drugs. However, it has been difficult to develop synthetic multicyclic peptides that that have desired biological activities. The Gao group will integrate molecular biology and synthetic chemistry to construct libraries of peptides with complex multicyclic structures. These synthetic multicyclic peptides will be screened for their abilities to inhibit bacterial proteins using phage display, a technology that allows identification of compounds that show specific desired biological activities. This interdisciplinary project will help train the next-generation of scientists by engaging students in research, including undergraduate students and high school interns. Phage display, a popular technology for screening peptide libraries, has been largely limited to the display of linear or simple disulfide-cyclized peptides. These peptides fall short in terms of structural complexity in comparison to peptide natural products, which often display multicyclic structures. In this studies, the Gao group aims to develop novel chemical strategies to construct multicyclic peptide libraries on the surfaces of bacteriophages. These strategies include developing and examining various protein conjugation chemistries, to be used in combination to effect sequential multicyclizations of phage-displayed peptides. Specifically, the research will capitalize on a newly developed ultrafast cysteine conjugation chemistry that crosslinks specific amino acid residues with high efficiency and site selectivity. These novel multicyclic peptide libraries will be used to screen and select for inhibitors of specific bacterial protein-protein interactions. If successful, this project will provide a powerful and broadly applicable strategy for inhibiting protein-protein interactions such as those that facilitate immune response evasion by bacterial pathogens.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.