RAPID: Exploring Covid-19 RNA Viral Targets By Graph-Theory-Based Modeling

新冠肺炎迫切需要的治疗和疫苗依赖于对复杂病毒机制的基本了解。该项目将确定病毒RNA两个区域的结构特性和药物结合潜力，这两个区域对于新冠肺炎基因组在宿主细胞的入侵和繁殖至关重要：负责制造尖峰蛋白和融合蛋白的基因。具体地说，该项目将开发基于图论的新的高效计算算法，用于识别新冠肺炎病毒基因组中当它们发生突变时改变RNA亚结构的亚区。鉴定这些亚区将有助于发现抗病毒抑制剂化合物。PI实验室已经开发的图论工具为RNA结构分析和设计提供了粗粒度的方法。PI将把这些工具与生物分子建模结合起来，以检查从SARS、MERS和其他病毒中已知的抗病毒抑制剂的治疗潜力。该项目将产生对核糖核酸病毒区域的结构性见解，并确定有助于在对抗新冠肺炎方面取得进展的关键核苷酸和候选抑制剂。这项研究对新冠肺炎以及未来可能出现的其他冠状病毒都有深远的影响。该项目为包括女性和少数民族在内的年轻科学家提供了独特的数学、生物、化学和科学计算方面的跨学科培训。研究成果将迅速与广大新冠肺炎研究界分享。由于病毒基因组序列和结构的高度保守性以及CRISPR技术的迅速崛起，RNA靶向方法具有治疗潜力。当蛋白质抑制化合物导致RNA病毒基因组本身入侵时，他们也提出了替代方案。这类能够显著改变RNA结构的化合物有望抑制病毒的入侵和复制。由于融合蛋白编码区包含一个参与移码机制的伪结(相互缠绕的碱基对)亚结构，因此确定破坏这种伪结的关键突变区域和相关化合物将是非常有价值的。该项目团队在核酸复合体的生物分子建模和模拟方面拥有丰富的经验，并开发了用于分析RNA基序、预测结构和设计新型RNA折叠的图论框架。图论框架将被扩展并应用于这个项目，通过确定RNA新冠肺炎病毒基因组中的关键区域和相关的化学抑制剂来应对新冠肺炎大流行，这些关键区域将干扰病毒融合到宿主细胞中和在宿主细胞内复制。凭借这一奖项，数学科学部的数学生物学项目和化学部的生命过程化学项目将资助纽约大学的施里克博士确定新冠肺炎病毒RNA的结构特性和药物结合潜力。这笔赠款是利用冠状病毒援助、救济和经济安全(CARE)法案提供的资金授予MPS.的补充资金。这一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。

The urgently needed treatments and vaccines for COVID-19 rely on a fundamental understanding of the complex viral apparatus. This project will determine the structural properties and drug-binding potential of two regions of the viral RNA essential for invasion and propagation of the COVID-19 genome in host cells: genes responsible for making spike and fusion proteins. Specifically, the project will develop new and efficient graph-theory based computational algorithms for identifying subregions in the COVID-19 viral genome that alter the RNA substructure when they are mutated. Identification of these subregions will aid in the discovery of anti-viral inhibitor compounds. Graph theory tools already developed in the PI’s lab offer coarse-grained approaches for RNA structural analysis and design. The PI will combine these tools with biomolecular modeling to examine the therapeutic potential of anti-viral inhibitors known from SARS, MERS, and other viruses. This project will produce structural insights into the RNA viral regions and identify critical nucleotides and candidate inhibitors that will help make progress against COVID-19. The research has profound impact to COVID-19 as well as other coronaviruses that could emerge in the future. The project offers unique interdisciplinary training in mathematics, biology, chemistry, and scientific computing for young scientists, including women and minorities. The research results will be shared rapidly with the COVID-19 research community at large.RNA-targeting approaches have therapeutic potential due to the high sequence and structure conservation of the viral genomes and the rapid emergence of CRISPR technology. They also present alternatives when protein-inhibiting compounds lead to invasion of the RNA viral genome itself. Such compounds that alter the RNA structure significantly are expected to inhibit viral invasion and replication. Because the fusion-protein coding region contains a pseudoknot (intertwined base-pair) substructure involved in a frame-shifting mechanism, the determination of critical mutation regions and associated compounds that destroy this pseudoknot will be invaluable. The project team has rich experience in biomolecular modeling and simulation of nucleic acid complexes and has developed a graph-theory framework for analyzing RNA motifs, predicting structures, and designing novel RNA folds. The graph-theory framework will be extended and applied in this project to address the COVID-19 pandemic by determining key regions in the RNA COVID-19 viral genome and associated chemical inhibitors that would interfere with viral fusion into and replication within host cells. With this award, the Mathematical Biology Program in the Division of Mathematical Sciences and the Chemistry of Life Processes Program in the Division of Chemistry are funding Dr. Schlick from New York University to determine the structural properties and drug-binding potential of the COVID-19 viral RNA.This grant is being awarded using funds made available by the Coronavirus Aid, Relief, and Economic Security (CARES) Act supplemental funds allocated to MPS.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.