Optimisation of a novel series of SARS-CoV-2 inhibitors

新冠肺炎大流行是近代史上最严重的全球卫生危机，英国有14万多人死亡，全球有500多万人死亡。尽管进行了广泛的疫苗接种计划，但在英国和全球范围内，这种病毒仍然具有传染性，住院率和死亡率仍然很高。index Therapeutics公司与利物浦大学和利物浦热带医学院合作，在药物发现弹射器的支持下，正在开发一系列新的药物来治疗冠状病毒，包括导致全球COVID-19大流行的SARS-CoV-2。这些新药通过靶向一种对病毒复制至关重要的关键蛋白酶起作用。这些抑制剂将有助于满足对新型抗病毒药物的迫切临床需求，这些药物可有效治疗突破性病例、未接种疫苗和高危患者（如正在接受抗癌治疗的患者），从而减少住院治疗和医疗保健系统的压力，并降低死亡率。这些化合物有可能治疗未来的SARS-CoV-2变体，并且由于不同冠状病毒的目标高度保守性，可能在预测未来的大流行中具有实用性。这项资助的目标是通过先导优化来开发现有的热门药物，以产生先进的药物样先导，这些先导在疗效模型中显示出体内概念证明，并且具有很高的临床前候选药物提名和安全有效治疗的发展潜力。这将通过应用一个明确确定的铅优化程序来实现，包括药物化学、酶学、病毒学、安全性分析和疗效评估。将开发一种使用人类肺细胞的创新气道类器官模型，并将其用于帮助将临床前数据转化为临床试验，并将在整个行业中提供更广泛的效用。

The COVID-19 pandemic is the most serious global health crisis in recent history with over 140,000 deaths in the UK and over 5 million deaths worldwide. Despite extensive vaccination programs, the virus remains transmissible with hospitalisation and mortality remaining high, both in the UK and globally.Infex Therapeutics, in partnership with the University of Liverpool and the Liverpool School of Tropical Medicine, and supported by the Medicines Discovery Catapult, is developing a novel series of drugs to treat coronavirus, including SARS-CoV-2, the cause of the global COVID-19 pandemic. These new drugs work by targeting a key protease essential for viral replication. These inhibitors will help meet a desperate clinical need for novel anti-viral agents which are effective in treating breakthrough cases, unvaccinated and high-risk patients such as those undergoing anti-cancer treatments, leading to reduced hospitalisation and pressure on healthcare systems, and lower death rates. The compounds have potential to treat future SARS-CoV-2 variants and may have utility for use in predicted future pandemics due to the highly conserved nature of the target across different coronaviruses.The objective for this grant is to develop existing hits through lead optimisation to generate advanced drug-like leads, which display in vivo proof of concept in efficacy models and have high potential for preclinical candidate nomination and onwards development towards a safe and effective treatment. This will be achieved by applying a clearly-identified lead-optimisation program including medicinal chemistry, enzymology, virology, safety profiling and efficacy assessment. An innovative airway organoid model using human lung cells will be developed and utilised to aid the translation of preclinical data into clinical trials and will provide broader utility across the industry.