Mechanism of Light-activated Antiviral Activity of Conjugated Polyelectrolyte Polymers and Oligomers

共轭聚电解质聚合物和低聚物的光激活抗病毒活性机制

• 批准号: 2105171
• 负责人: Eva Chi
• 金额: $ 55万
• 依托单位: University of New Mexico
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2105171&HistoricalAwards=false
• 关键词: Mechanism; Light; activated; Antiviral; Activity

NON-TECHNICAL SUMMARYThe health and economic devastation brought on by the Covid-19 pandemic underscores the urgent need to develop a multifaceted pandemic planning and response to stop viral outbreaks. This project takes a materials science and engineering approach to develop broad-spectrum antiviral materials that work against many viruses without inducing resistance. The research team has shown that a class of conjugated polymers and oligomers exhibit remarkable near-UV/visible light-activated killing of bacteriophages and the SARS-CoV-2 coronavirus that causes the Covid-19 pandemic; greater than 99.9999% viral inactivation is routinely achieved. This project focuses on elucidating the antiviral mechanism of the conjugated compounds. Propensity of the compounds to interact with and disrupt the structures and functions of several viral targets, including spike and capsid proteins, viral membrane, and RNA, will be studied using a suite of experimental techniques. Combined with computational simulations, a fundamental understanding of the interactions between the synthetic compounds with viral components that are responsible for their antiviral activity will be gained. Such insights will guide the rational design of new compounds with optimal antiviral properties to slow the spread of infections. This project will also identify virus components to target and degrade that will result in viral inactivation. Taken together, this project will contribute towards the development of highly effective and broad-spectrum antiviral materials for healthcare workers and for the public and will transform our ability to prepare for and respond to current and future outbreaks.TECHNICAL SUMMARYThe goal of this project is to gain a fundamental understanding of the intermolecular interactions between novel synthetic conjugated polyelectrolyte polymers (CPEs) and oligomers (OPEs) with various viral assemblies that give rise to their remarkable light-activated broad-spectrum antiviral activity. CPEs and OPEs have recently been shown to be highly efficient at inactivating the SARS-CoV-2 virus that causes the Covid-19 pandemic. The proposed project focuses on elucidating the antiviral mechanism of the compounds with the ultimate goal of guiding the rational design of novel materials with optimal properties. The CPEs and OPEs are charged and amphiphilic in nature, which provides them the ability to interact with and potentially disrupt the structures, and thereby functions, of multiple virial targets. Additionally, light-activated photosensitizing activity of the compounds can further contribute to their antiviral efficacy. Specifically, the propensity of CPEs and OPEs with varying backbones, chain length, side and end groups, charge density and distribution to interact with and disrupt the structures and functions of several viral macromolecular assemblies, including protein assemblies, membranes, and nucleic acids. The multidisciplinary team will use a suite of biophysical and materials characterization methods to study the interactions between CPEs and OPEs and viral targets, from molecular structural scale to macroscopic property levels, combined synergistically with closely related simulations. Comparing our findings with functional assays and antiviral activities will enable us to elucidate the toxicity mechanism and structure-function relationship of these novel synthetic antiviral materials.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.

2019冠状病毒病（COVID-19，即2019冠状病毒病）大流行对健康和经济造成的破坏，突显出迫切需要制定多方面的大流行规划和应对措施，以阻止病毒爆发。该项目采用材料科学和工程方法来开发广谱抗病毒材料，这些材料可以对抗许多病毒而不会诱导耐药性。研究小组已经证明，一类共轭聚合物和低聚物表现出显着的近紫外/可见光激活的噬菌体和导致Covid-19大流行的SARS-CoV-2冠状病毒的杀伤作用;常规实现超过99.9999%的病毒灭活。本项目的重点是阐明共轭化合物的抗病毒机制。将使用一套实验技术研究化合物与几种病毒靶标（包括刺突蛋白和衣壳蛋白、病毒膜和RNA）相互作用并破坏其结构和功能的倾向。结合计算机模拟，将获得对合成化合物与负责其抗病毒活性的病毒组分之间相互作用的基本理解。这些见解将指导具有最佳抗病毒特性的新化合物的合理设计，以减缓感染的传播。本项目还将确定靶向和降解的病毒组分，这将导致病毒灭活。综合起来看，本项目将为卫生保健工作者和公众开发高效、广谱的抗病毒材料做出贡献，并将改变我们对当前和未来疫情的准备和响应能力。技术概述本项目的目标是对新型合成共轭聚合物（CPE）和低聚物（OPEs）之间的分子间相互作用有一个基本的了解具有各种病毒组装体，这些病毒组装体产生它们显著的光激活广谱抗病毒活性。CPE和OPEs最近被证明在灭活导致Covid-19大流行的SARS-CoV-2病毒方面非常有效。该项目的重点是阐明化合物的抗病毒机制，最终目标是指导具有最佳性能的新型材料的合理设计。CPE和OPEs本质上是带电的和两亲的，这使它们能够与多个维里靶相互作用并潜在地破坏其结构，从而破坏其功能。此外，化合物的光活化光敏活性可进一步有助于其抗病毒功效。具体而言，具有不同主链、链长、侧基和端基、电荷密度和分布的CPE和OPEs与几种病毒大分子组装体（包括蛋白质组装体、膜和核酸）相互作用并破坏其结构和功能的倾向。多学科团队将使用一套生物物理和材料表征方法来研究CPE和OPEs与病毒靶标之间的相互作用，从分子结构尺度到宏观性质水平，与密切相关的模拟协同结合。将我们的研究结果与功能测定和抗病毒活性进行比较，将使我们能够阐明这些新型合成抗病毒材料的毒性机制和结构-功能关系。该奖项反映了NSF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。