Alternative attacks against SARS-CoV-2 proteins: Identifying and developing orthogonal therapeutic strategies using computational structural biology and synthetic chemistry

针对 SARS-CoV-2 蛋白的替代攻击：利用计算结构生物学和合成化学识别和开发正交治疗策略

• 批准号: 553704-2020
• 负责人: Trant, John
• 金额: $ 3.64万
• 依托单位: University of Windsor
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=704078
• 关键词: Alternative; attacks; against; SARS; CoV

This project is a collaboration between the Trant research group at the University of Windsor, which focuses on computational and synthetic medicinal chemistry (with particular focus on the development of cyclic peptide and carbohydrate-based therapeutics); and Devonian Health Group (DHG), a Montreal-based pharmaceutical company. SARS-CoV-2, the causative agent for COVID-19, is essentially a self-replicating machine made up of proteins and lipids. The proteins have all been identified, and recent work has shown that many of them interact with human proteins when they are in an infected cell. These interactions could provide the basis for designing drugs that can bind to the SARS-CoV-2 proteins, preventing them from doing their job. Many of the immediate efforts are aimed at repurposing approved drugs, but the SARS-CoV-2 proteins are very different from the normal targets of these drugs; one of the major challenges is that these proteins lack well-defined pockets and clefts that are the normal targets of normal drugs, and many are coated in sugars that make the surface challenging to access for antibodies and drugs. However, they are perfect targets for unconventional approaches such as cyclic peptides and repurposed proteins. The Trant group is using a combination of computational modeling to understand the interactions between these proteins and small molecules with the eventual dual goals of developing therapeutics and providing a better understanding of SARS-CoV-2 molecular biology. Trant and DHG already have an active collaboration in antimicrobial science and will be leveraging this connection to further investigate and develop any molecules identified by the team. SARS-CoV-2 is a challenging target, and we will need to explore all options for treatment, including innovative biologics that we will be investigating in this project, so that we as Canadians can safely and confidently resume our normal lives.

该项目是温莎大学的Trant研究小组与Devonian Health Group（DHG）之间的合作，该研究小组专注于计算和合成药物化学（特别关注环肽和碳水化合物疗法的开发），Devonian Health Group（DHG）是一家总部位于伦敦的制药公司。SARS-CoV-2是COVID-19的病原体，本质上是一种由蛋白质和脂质组成的自我复制机器。这些蛋白质都已经被鉴定出来，最近的研究表明，当它们在受感染的细胞中时，其中许多蛋白质与人类蛋白质相互作用。这些相互作用可以为设计能够与SARS-CoV-2蛋白结合的药物提供基础，从而阻止它们发挥作用。许多立即的努力旨在重新利用已批准的药物，但SARS-CoV-2蛋白与这些药物的正常靶点非常不同;主要挑战之一是这些蛋白质缺乏明确的口袋和裂缝，而这些口袋和裂缝是正常药物的正常靶点，而且许多蛋白质被糖包裹，使表面难以接触抗体和药物。然而，它们是非常规方法的理想目标，如环肽和再利用蛋白质。Trant小组正在使用计算建模的组合来了解这些蛋白质和小分子之间的相互作用，最终的双重目标是开发治疗方法并更好地了解SARS-CoV-2分子生物学。Trant和DHG已经在抗菌科学方面进行了积极的合作，并将利用这种联系进一步研究和开发团队确定的任何分子。SARS-CoV-2是一个具有挑战性的目标，我们将需要探索所有治疗方案，包括我们将在该项目中研究的创新生物制剂，以便我们加拿大人能够安全和自信地恢复正常生活。