Repurposing approved drugs as potent antiviral combinations to treat COVID-19 disease

SARS-CoV-2是自2019年12月出现以来摧毁了大多数国家的全球大流行的罪魁祸首。已作出巨大努力，分别生产预防和治疗感染的疫苗和药物。疫苗开发以前所未有的速度进行，并于2020年底和2021年初紧急批准了一些疫苗。一些药物也被证明对严重的COVID-19疾病有治疗作用，其中大多数是免疫调节剂。然而，除了瑞德西韦和单克隆抗体鸡尾酒之外，抗病毒治疗的成功很少。因此，本项目将寻求弥合这一差距，并寻求确定具有增强抗病毒活性的新型药物组合，以对抗COVID-19疾病的病原体SARS-CoV-2。我们汇集了来自贝尔法斯特女王大学、利物浦大学和牛津大学的强大专家团队。我们将首先筛选一个由140种已知对SARS-CoV-2具有抗病毒活性的药物组成的定制文库，以寻找增强其抗病毒潜力的组合。然后将对最佳组合进行一系列强有力的体外和体内试验，以验证其潜力。这些数据将为向UK-CTAP提出进入临床试验的强烈建议提供依据。同时，我们将评估药物组合引发耐药突变的倾向，这是将在全球大规模使用的药物的重要考虑因素。最后，同时，我们已经确定了2个尚未进行联合药物筛选的大型药物文库。我们将利用我们强大的药物筛选平台来确定备用的候选药物组合，以确保未来有针对SARS-CoV-2的抗病毒药物管道。

SARS-CoV-2 is responsible for the worldwide pandemic that has devasted most countries since it emerged in December 2019. Huge efforts have been made to generate vaccines and drugs to prevent and treat infection, respectively. Vaccine development has proceeded at an unprecendent pace and emergency authorisation was given for a number of vaccines in late 2020 and early 2021. Some drugs have also been shown to have therapeutic benefits against severe COVID-19 disease, most of which are immunemodulators. However, there has been very little success with antiviral therapeutics, with the notable exceptions of remdesivir and monoclonal antibody cocktails. This project, therefore, will seek to bridge this gap and seeks to identify novel drug combinations with enhanced antiviral activities against SARS-CoV-2, the causative agent of COVID-19 disease. We have assembled a very strong team of expertis from Queen's University Belfast, University of Liverpool and University of Oxford. We will initially screen a bespoke library of 140 drugs with known antiviral activity against SARS-CoV-2 for combinations that enhance their antiviral potential. The best combinations will then undergo a robust series of in vitro and in vivo protocols to validate their potential. The data will provide the rationale to make strong recommendations to UK-CTAP for progression to clinical trials. In parallel, we will evaluate the propensity of the drug combinations to elicit drug-resistant mutants, which is an important consideration for drugs that will be used on a massive scale globally. Finally, and in parallel, we have identified 2 large drug libraries that have not been subjected yet to combination drug screening. We will exploit our robust drug screening platform of protocols to identify back-up drug combination candidates to ensure a pipeline of antiviral drugs against SARS-CoV-2 for the future.