Expanding the Chemical Space of Phage isplay

蛋白质在复杂的人类生物学和生物功能失调中起着重要的作用。在生物学中使用化学工具使科学家能够控制特定蛋白质的行为。噬菌体展示是一种用于研究蛋白质的技术。蛋白质,蛋白质?肽和蛋白质？DNA的相互作用。噬菌体展示使用噬菌体（感染细菌的病毒）将蛋白质与编码它们的遗传信息连接起来。噬菌体展示仅限于产生自然界中存在的多肽。该项目通过提供从化学改变的氨基酸制造肽的新途径，扩展了肽在控制蛋白质行为方面的应用能力。来自罗克斯伯里社区学院的学生和来自大波士顿地区的高中生积极参与研究工作，用化学来解决生物挑战。重要的是，该项目包括对配体-蛋白质结合机制的详细生化和结构研究，这可能为合成分子识别蛋白质提供新的指导原则，并最终为生物功能障碍提供新的治疗方法。有了这个奖项，生命过程化学项目将资助波士顿学院的高建民教授开发化学修饰的噬菌体文库，并探索它们靶向小分子和天然肽的蛋白质的潜力。噬菌体展示作为一种基因编码的筛选平台，在很大程度上限制了可展示分子的多肽，这些多肽含有蛋白质原氨基酸，对于没有明确识别区域的蛋白质，往往无法产生高亲和力的探针和抑制剂。高博士通过修饰噬菌体展示肽以呈现非自然功能来克服这一限制。巧妙地利用生物相容性和化学选择性反应对噬菌体进行修饰，有望产生新的噬菌体文库，每个肽成员携带两种不同的设计功能。基于这种噬菌体修饰的创新技术，高博士和他的研究团队寻求开发一种“配体成熟”方案，该方案允许以配体-肽偶联物的形式将低亲和力配体轻松转化为靶蛋白的强效结合物。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Proteins play important roles in complex human biology and biological malfunction. The use of chemical tools in biology allows scientists to control of the behavior of specific proteins. Phage display is a technique used to study protein?protein, protein?peptide, and protein?DNA interactions. Phage display uses bacteriophages (viruses that infect bacteria) to connect proteins with the genetic information that encodes them. Phage display has been limited to the creation of peptides that occur in nature. This project expands the capabilities of peptides that can be of use in controlling protein behavior by providing a new path to making peptides from amino acids that have been chemically altered. Students from Roxbury Community College and high school students from the Greater Boston area are actively engaged in the research efforts to use chemistry to solve biological challenges. Importantly, this project includes detailed biochemical and structural studies of the ligand-protein binding mechanisms that may yield new guiding principles for protein recognition by synthetic molecules and eventually, new treatments for biological malfunction. With this award, the Chemistry of Life Processes Program is funding Professor Jianmin Gao at Boston College to develop chemically-modified phage libraries and explore their potential for targeting proteins that have eluded small molecules and natural peptides. Phage display, as a genetically encoded screening platform, has largely limited the displayable molecules to peptides comprising proteinogenic amino acids, which often fall short in generating high-affinity probes and inhibitors for proteins that do not have a well-defined recognition region. Dr. Gao overcomes this limitation by modifying phage-displayed peptides to present unnatural functionalities. Clever use of biocompatible and chemoselective reactions for phage modification is expected to yield novel phage libraries, with each peptide member carrying two distinct designer functionalities. Building on this innovative technology for phage modification, Dr. Gao and his research team seek to develop a "ligand maturation" protocol that allows facile conversion of low-affinity ligands into potent binders of the target protein in the form of ligand-peptide conjugates.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.