Macrocyclic Inhibitors of the SARS-CoV-2 / ACE-2 Interaction in COVID-19

COVID-19 中 SARS-CoV-2 / ACE-2 相互作用的大环抑制剂

• 批准号: 555123-2020
• 负责人: Grandbois, Michel
• 金额: $ 3.64万
• 依托单位: Université de Sherbrooke
• 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=705595
• 关键词: Macrocyclic; Inhibitors; SARS; CoV; ACE

The goal of this proposal is to develop and optimize new drugs able to prevent coronavirus entry into human airway cells. This project is a collaboration between Université de Sherbrooke and Nuchem Therpeutics (Montreal), University of British Columbia (Vancouver) and Collège de Shawinigan. Through the current pandemic, we have to humbly recognize that we were ill-prepared for such outbreak. Its human, economic and strategic impacts are global and will be durable. This pandemic has nevertheless mobilized the scientific community at all levels to better understand the mechanisms involved in SARS-CoV-2 infection and find solutions to manage the disease and its consequences. In terms of treatment options, short-term solutions in the form of repurposed drugs or biologics (e.g., antibodies) could possibly provide much-needed relief. This is an emergency response and every possible drug already on the market or in clinical development is being tested. However these drugs were not optimized for SARS-CoV-2. In the mid-term, vaccination will hopefully provide a means to prevent novel infections and carries hopes for large scale prevention. Thus, there is currently no drug specifically targeting SARS-CoV-2, and little know-how to be implemented in potential future coronavirus epidemics. Ultimately, these efforts are expected to lead to a class of drugs known as entry inhibitors, with the potential to not only cure patients infected by SARS-CoV-2 by stopping the virus from penetrating cells, but also to prevent healthy people from being infected. This proposal exploits novel macrocyclic inhibitors targeting protein-protein interactions between the Spike protein of SARS-CoV-2, and its host receptor, ACE-2. The first step of the project is to computationally design macrocycles that mimic motifs found on two proteins involved in viral entry. The second step is to synthesize them, while the third is to test their ability to block the interaction between the two proteins, and demonstrate their ability to block viral infection in cells.

该提案的目标是开发和优化能够阻止冠状病毒进入人类的新药 气道细胞。该项目是舍布鲁克大学与 Nuchem Therpeutics（蒙特利尔）、不列颠哥伦比亚大学（温哥华）和 Collège de Shawinigan 之间的合作。 通过当前的大流行，我们必须谦虚地认识到，我们对这种爆发的准备不足。其人类、经济和战略影响是全球性的，并且是持久的。然而这场疫情 动员各级科学界更好地了解 SARS-CoV-2 感染的机制，并找到管理该疾病及其后果的解决方案。在治疗选择方面， 重新利用药物或生物制品（例如抗体）形式的短期解决方案可能会提供 急需的救济。这是一种紧急应对措施，所有已经上市或处于临床开发阶段的可能药物都正在接受测试。然而，这些药物并未针对 SARS-CoV-2 进行优化。从中期来看，疫苗接种有望提供一种预防新感染的手段，并带来大规模接种的希望 预防。因此，目前还没有专门针对 SARS-CoV-2 的药物，而且对于如何治疗也知之甚少。 在未来潜在的冠状病毒流行中实施。 最终，这些努力预计将产生一类被称为进入抑制剂的药物，它不仅有可能通过阻止病毒穿透细胞来治愈感染 SARS-CoV-2 的患者，而且有可能 防止健康人被感染。该提案利用了新型大环抑制剂 SARS-CoV-2 的刺突蛋白与其宿主受体 ACE-2 之间的蛋白质-蛋白质相互作用。 该项目的第一步是通过计算设计大环化合物，模拟在病毒进入所涉及的两种蛋白质上发现的基序。 第二步是合成它们，第三步是测试它们阻断两种蛋白质之间相互作用的能力，并证明它们阻断细胞内病毒感染的能力。