Development of a SARS-CoV-2 spike protein binding assay using human epithelial cells for COVID-19 therapy discovery and development

当前COVID-19大流行的紧迫性需要尽可能快速和安全地开发新的治疗方法。无论从参与这些努力的许多实验室中得出什么结果，都需要以各种方式进行测试，以帮助我们知道它们是否会在给可能感染SARS-CoV-2的人时起作用，这种病毒会导致COVID-19。对于导致这种疾病的病毒，它需要进入我们的一些细胞，在那里它可以生存，繁殖，然后感染体内的其他细胞。要做到这一点，病毒首先需要附着在我们的细胞上。为此，它使用病毒外部的一个特定部分，即“刺钉”，固定在我们细胞外部的特殊部分（“受体”）上，如果适合，就像钥匙适合锁一样。这个项目将重述病毒感染的第一个重要步骤，使我们能够在“培养皿”中测试新的治疗方法，以支持针对COVID-19的治疗发现工作。虽然支持这种发展的模型是可用的，使用具有纯化的细胞组分的系统（使用病毒用于进入的“受体”），或者使用完整的病毒，但是缺乏可以以简单的方式用于测试药物和疫苗接种产生的抗体对病毒进入人类细胞的特定步骤的影响的细胞模型。我们打算使用人类细胞（包括肺内衬细胞，已知这是病毒进入的关键部位）和SARS-CoV-2纯化的刺突蛋白来开发一种“基于细胞”的模型。这种生物模型将使我们和我们的工业合作伙伴能够在对病毒感染至关重要的非常具体的步骤上测试他们的疗法。我们将使用先进的成像技术来可视化病毒刺突蛋白与人类细胞的结合，然后我们将能够测试药物或其他药物（如疫苗产生的抗体）如何影响病毒进入的这一特定步骤。这将使候选药物能够被选为治疗药物，开发药物的改进版本或支持选择产生针对病毒的保护性抗体的疫苗。

The urgency of the current COVID-19 pandemic needs new treatments to be developed as quickly and as safely as possible. Whatever comes out of the many labs involved in these efforts needs to be tested in a variety of ways to help us know if they will work when given to people who might be infected by SARS-CoV-2, the virus which causes COVID-19\. For the virus to cause this disease, it needs to get inside some of our cells where it can survive, multiply and then infect other cells in the body. To do this, the virus first needs to latch onto our cells. For this, it uses a specific part on the outside of the virus, the 'spike', to fasten onto special parts on the outside of our cells ('receptors') to which if fits, like a key fits a lock.This project will recapitulate this first essential step of viral infection allowing us to test new treatments 'in a dish' in order to support the therapeutic discovery effort against COVID-19\. Whilst models to support this development are available using systems with purified components of cells (using the 'receptors' the virus uses for entry), or, using the intact virus, there is a lack of cellular models that can be used in a simple manner for testing the impact of drugs, and antibodies arising from vaccination, on specific steps of viral entry into human cells. We intend to develop a 'cell-based' model using human cells (including cells lining the lung, which are known to be a key site of entry for the virus) and SARS-CoV-2 purified spike protein. This biological model will enable us and our industrial partners to test their therapeutics on a very specific step vital for viral infection. We will use advanced imaging techniques to visualise this binding of the viral spike protein to human cells, and, we will then be able to test how drugs, or other agents such as antibodies generated by a vaccine, impact this specific step of viral entry. This will then enable candidate drugs to be selected as therapeutics, improved versions of drugs to be developed or support the selection of vaccines that generate protective antibodies against the virus.