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

这项建议的目标是开发和优化能够防止冠状病毒进入人类的新药 呼吸道细胞。该项目是舍布鲁克大学和纽亨大学(蒙特利尔)、不列颠哥伦比亚大学(温哥华)和夏维尼根学院(Collège de Shawinigan)的合作项目。 在当前的大流行中，我们必须谦虚地认识到，我们对这种疫情的爆发准备不足。其对人力、经济和战略的影响是全球性的，并将是持久的。尽管如此，这场大流行 动员各级科学界更好地了解SARS-CoV-2感染的机制，并找到解决办法来管理这一疾病及其后果。在治疗选择方面， 重新调整用途的药物或生物制品(例如抗体)形式的短期解决方案可能会提供 急需的解脱。这是一种紧急反应，已经上市或正在临床开发的每一种可能的药物都在进行测试。然而，这些药物并没有针对SARS-CoV-2进行优化。在中期，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，也几乎不知道如何使用 在未来可能的冠状病毒流行中实施。 最终，这些努力有望导致一类被称为进入抑制剂的药物，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，而且还可能 防止健康人被感染。这一提议利用了新的大环抑制剂靶向。 SARS-CoV-2刺突蛋白与宿主受体ACE-2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出模仿病毒进入过程中两种蛋白质上发现的基序的大环。 第二步是合成它们，第三步是测试它们阻止这两种蛋白质之间相互作用的能力，并展示它们阻止细胞中病毒感染的能力。

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.