DNA-Scaffolded Peptides as High-Affinity Reagents

非技术：该奖项由乔治亚大学材料研究部生物材料项目颁发，旨在通过单链DNA上的支架肽开发抗体模拟平台。该奖项由生物科学理事会分子和细胞生物科学部的遗传机制项目共同资助。抗体对促进生物医学研究的发现至关重要；然而，它们有各种各样的缺点，引起了人们对生物医学研究中获得高质量抗体的担忧。需要替代的和更强大的聚合物分子识别来推动发现工作向前发展。核酸聚合物作为高亲和试剂已显示出巨大的前景；然而，它们缺乏化学功能限制了它们作为受体与蛋白质竞争的能力。通过将核酸聚合物的可进化分子支架与多种蛋白质功能相结合，PI旨在为生物医学研究开发一类新的抗体模拟物，这可能会解决分子靶点可用抗体的严重缺陷。这些研究工作将与在高中、本科和研究生阶段的教育和培训推广相结合，以协助培养有能力解决跨学科研究问题的下一代科学家。技术：本提案描述了通过DNA上的支架肽开发抗体模拟物的体外选择平台的研究。与传统抗体相比，核酸适体提供了许多优势；然而，它们的官能团缺陷限制了它们与蛋白亲和试剂性能匹配的潜力。通过将核酸聚合物的可进化分子支架与蛋白质功能相结合，该研究人员将使用这类聚合物来模拟自然界在蛋白质-蛋白质界面上使用的异价和多价方法。研究者将使用酶的策略，以序列特异性地结合独特的肽片段沿着DNA模板。这种方法将使ssDNA支架和所显示肽的身份同步进化，以实现对蛋白质靶点的分子识别。如果成功，这种新型仿生聚合物可以帮助解决生物医学研究中高亲和力试剂的缺陷。这些研究工作将与高中、本科和研究生水平的教育和培训推广相结合。

Non-technical: This award by the Biomaterials program in the Division of Materials Research to University of Georgia is to develop a platform for antibody mimetics by scaffolding peptides on single stranded DNA. This award is cofunded by the Genetic Mechanisms program in the Division of Molecular & Cellular Biosciences in the Directorate for Biological Sciences. Antibodies are essential to facilitating discoveries in biomedical research; however, they have a variety of shortcomings that have elicited concerns over accessibility to high-quality antibodies for biomedical research. Alterative and more robust polymers for molecular recognition are needed to drive discovery efforts forward. Nucleic acid polymers have demonstrated immense promise as high-affinity reagents; however, their lack of chemical functionality limits their ability to compete with proteins as receptors. By merging the evolvable molecular scaffold of nucleic acid polymers with diverse protein functionality, the PI aims to evolve a new class of antibody mimetics for biomedical research, which may address the critical deficit of available antibodies for molecular targets. These research efforts will be coupled with educational and training outreach at the high school, undergraduate, and graduate levels in order to assist in the development of a future generation of scientists that are properly equipped to tackle interdisciplinary research problems.Technical: This proposal describes research to develop an in vitro selection platform for antibody mimetics by scaffolding peptides on DNA. Nucleic acid aptamers have provided numerous advantages over traditional antibodies; however, their functional group deficit limits their potential to match the performance of proteinogenic affinity reagents. By merging the evolvable molecular scaffold of nucleic acid polymers with protein functionality, this investigator will use this class of polymers to mimic the hetero- and multivalent approach nature uses at protein-protein interfaces. The investigator will use an enzymatic strategy to sequence-specifically incorporate unique peptide fragments along a DNA template. This approach will enable the concomitant evolution of the ssDNA scaffold and the identity of the displayed peptides to achieve molecular recognition of protein targets. If successful, this new class of biomimetic polymers could aid in addressing the deficit of high-affinity reagents for biomedical research. These research efforts will be coupled with educational and training outreach at the high school, undergraduate, and graduate levels.