Expanding the Chemical Space of Phage isplay

蛋白质在复杂的人体生物学和生物功能障碍中发挥着重要作用。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-蛋白质、蛋白质-多肽和蛋白质-DNA相互作用的技术。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。噬菌体展示仅限于创造自然界中存在的多肽。该项目通过提供一种新的途径，从经过化学改变的氨基酸制造多肽，从而扩展了可用于控制蛋白质行为的多肽的能力。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使用化学来解决生物挑战的研究工作。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，这些机制可能为合成分子识别蛋白质产生新的指导原则，并最终产生治疗生物功能障碍的新方法。通过这一奖项，生命过程化学计划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，并探索其靶向小分子和天然多肽的蛋白质的潜力。噬菌体展示作为一个基因编码的筛选平台，在很大程度上将可展示的分子限制在含有蛋白性氨基酸的多肽上，这些多肽往往不能为没有明确识别区域的蛋白质产生高亲和力的探针和抑制剂。高博士通过修改噬菌体展示的多肽来呈现非自然的功能，从而克服了这一限制。巧妙地利用生物相容和化学选择性反应进行噬菌体修饰有望产生新的噬菌体文库，每个肽成员携带两个不同的设计者功能。在这项创新的噬菌体修饰技术的基础上，高博士和他的研究团队寻求开发一种“配体成熟”方案，允许低亲和力的配体以配体-多肽结合物的形式轻松转化为目标蛋白的有效结合剂。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.