Collaborative Research: Nucleobase-Modified PNA for Sequence Selective Triple-Helical Recognition of Non-Coding RNA

合作研究：核碱基修饰的 PNA 用于非编码 RNA 的序列选择性三螺旋识别

• 批准号: 2107911
• 负责人: James MacKay
• 金额: $ 30万
• 依托单位: Elizabethtown College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2107911&HistoricalAwards=false
• 关键词: Collaborative; Research; Nucleobase; Modified; PNA

With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professors Eriks Rozners of SUNY Binghamton and James A. MacKay of Elizabethtown College are studying new methods for molecular recognition of biologically significant non-coding ribonucleic acid (RNA). With the onset of biochemical technologies such as CRISPR-Cas9 for DNA-editing, and the challenges associated with emerging pathogens such as the SARS-CoV-2 virus (novel coronavirus), RNA (ribonucleic acid) chemistry and biochemistry is at the forefront of research. We know that less than 2% of deoxyribonucleic acid (DNA) encodes for functional proteins, while over 70% of DNA is transcribed into RNA. The non-coding RNAs play important yet not fully understood roles in regulation of biological processes. Selective recognition, imaging, and functional regulation of such RNAs will be highly useful for fundamental science and practical applications in biotechnology. This project aims to establish new ways of targeting double-stranded RNA, which has been a long-standing problem and practical limitation in RNA biochemistry. Importantly, the project will be broader in its impact through expanding interdisciplinary collaborative research across traditional institutional boundaries and fostering the training and development of a diverse, globally competitive STEM (science, technology, engineering and mathematics) workforce through research and mentoring activities. The collaboration continues a 5 year partnership that has established a bridge for Elizabethtown College (a primarily undergraduate institution) students, especially women, minorities, and first generation college students for transitioning from undergraduate studies to advanced graduate studies at a research university. Work will contine toward improving STEM education of undergraduate and graduate students, and offer unique training for post-graduate students interested in exploring careers at a primarily undergraduate institution. The development of sequence-selective RNA binders is important for understanding the biochemistry of non-coding RNAs and may strongly impact fundamental RNA biology and practical applications in biotechnology and synthetic biology. This collaborative study will develop new derivatives of peptide nucleic acid (PNA) that are potentially capable of recognizing the entire Hoogsteen face of Watson-Crick base pairs of double-stranded RNA. This is to be achieved by development of new nucleobases and binding modes that place two anti-parallel PNA strands in the major groove, each hydrogen-bonding to their respective RNA strand. The properties of the new PNAs will be optimized using synthetic organic chemistry to promote recognition of diverse sequences of double-stranded RNA, which has the potential to solve a long-standing problem in molecular recognition of RNA. If successful, this research will enable a variety of applications, such as, imaging and functional control of regulatory RNA, designer riboswitches for synthetic biology, and inhibition of biologically important RNA for fundamental studies.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.

在化学过程中的化学过程（CLP）方案的支持下，SUNY BINGHAMTON的Eriks Rozner教授和Elizabethtown College的James A. Mackay正在研究分子识别生物具有重要意义的非编码非编码核糖核酸（RNA）的新方法。随着用于DNA编辑的CRISPR-CAS9等生化技术的发作，以及与SARS-COV-2病毒（新型冠状病毒）等新兴病原体相关的挑战，RNA（核糖核酸）化学和生物化学是研究的最前沿。 我们知道，不到2％的脱氧核糖核酸（DNA）编码功能蛋白，而超过70％的DNA被转录为RNA。非编码RNA在调节生物过程中起重要但尚未完全了解角色。对此类RNA的选择性识别，成像和功能调节对于生物技术中的基本科学和实际应用将非常有用。该项目旨在建立针对双链RNA的新方法，这是RNA生物化学的长期问题和实际限制。重要的是，通过扩大传统机构界限的跨学科合作研究，并通过研究和辅导活动扩大跨学科的合作研究，并促进多样化，全球竞争性的STEM（科学，技术，工程和数学）员工的培训和开发，从而促进该项目的影响。 该合作持续了5年的合作伙伴关系，该伙伴关系为伊丽莎白镇学院（主要是本科机构）的学生建立了桥梁，尤其是妇女，少数民族和第一代大学生，用于从本科学习过渡到研究大学的高级研究生研究。工作将包括改善本科生和研究生的STEM教育，并为有兴趣在本科机构探索职业的研究生提供独特的培训。序列选择性RNA粘合剂的开发对于理解非编码RNA的生物化学非常重要，并且可能会对生物技术和合成生物学中的基本RNA生物学和实际应用产生强烈影响。这项协作研究将开发新的肽核酸（PNA）的衍生物，这些肽核酸（PNA）可能能够识别双链RNA的Watson-Crick碱基对的整个Hoogsteen面。这是通过开发新的核碱基和结合模式来实现的，该模式将两个抗平行的PNA链放在主要的凹槽中，每种氢键键入各自的RNA链。新PNA的特性将使用合成有机化学进行优化，以促进对双链RNA的不同序列的识别，这有可能解决RNA分子识别的长期存在问题。如果成功的话，这项研究将实现各种应用，例如调节性RNA的成像和功能控制，设计师的核糖开关用于合成生物学，以及抑制基本研究的生物学重要RNA。这项奖项反映了NSF的法规任务，并被认为是通过基金会的知识优点和广泛的智力综述的评估来通过评估来进行评估。