Hit-to-lead optimisation of fragment hits targeting SARS-CoV-2 non structural protein 10 using structure-based drug design

冠状病毒可能已经困扰人类几个世纪了。他们造成的普通感冒病例约占所有病例的25%。在过去的20年里，各种冠状病毒的暴发都具有严重的威胁，如中国的SARS暴发，感染人数为8000人，死亡率约为10%。紧随其后的是2012年在沙特阿拉伯和2015年在韩国爆发的另一起疫情，迄今造成约2500人感染，死亡率为34%。这种新的冠状病毒被命名为MERS，因为它起源于中东。导致当前新冠肺炎大流行的最新冠状病毒名为SARS-CoV-2，已导致全球5.5亿多人感染，620多万人死亡。然而，非官方估计报告的感染率和死亡率要高得多。很难预测我们是否会在今年冬天和以后面临进一步的冠状病毒高峰，以及病毒将发生多大程度的变异并逃脱疫苗提供的保护。未来通过将相关病毒从动物传播给人类而发生更多冠状病毒暴发的风险也很高。因此，重要的是研究冠状病毒，以了解它们如何感染人类，以及如何通过开发疫苗或药物(如结合和抑制冠状病毒蛋白的小分子药物)来治疗或预防这些感染，并防止它们在人体内繁殖。SARS-CoV-2有超过25种不同的蛋白质，可分为三类。有一类蛋白质被称为非结构蛋白质，这些蛋白质参与了病毒的许多新复制和对其他人类的感染。因此，我们决定研究其中一种非结构蛋白，命名为非结构蛋白10(NSP10)。虽然它是一种相对较小的蛋白，但它至少激活了另外两种非结构病毒蛋白(nsp14和nsp16)，没有这两种蛋白，病毒就不能繁殖。通过阻断NSP10，我们可以同样地阻断这两种病毒蛋白，病毒就不再是‘活的’。在这个项目中，我们建议在以前工作的基础上开发与NSP10结合并阻断NSP10作用的抑制剂。在未来，这些抑制剂可能会与其他药物结合并阻止SARS-CoV-2中存在的其他蛋白质，从而产生更有效的药物组合。通过这种方法，我们希望不仅可以抗击SARS-CoV-2，还可以抗击可能在可预见的未来导致新爆发的密切相关的新型冠状病毒。

Coronaviruses have probably haunted humans for several centuries. They are responsible for approximately 25% of all cases of the common cold. In the last 20 years there have been various coronavirus outbreaks representing serious threats such as the SARS outbreak in China with 8000 infections and a mortality rate of ca. 10%. This was followed by another outbreak occurring in Saudi Arabia in 2012 and South Korea in 2015 causing ca. 2500 infections so far with a mortality rate of 34%. This novel coronavirus was named MERS, as it originated from the Middle East. The most recent novel coronavirus, named SARS-CoV-2 that is causing the current Covid-19 pandemic has caused more than 550 million infections and more than 6.2 million deaths worldwide. However, unofficial estimates report much higher infection and mortality rates. It is difficult to predict whether we will face further coronavirus peak this winter and beyond, and how much the virus will mutate and escape the protection afforded by vaccines. The risk is also high that additional coronavirus outbreaks will occur in the future, through transmission of related viruses from animals to humans. It is therefore important to study coronaviruses to understand how they infect humans and how these infections can be treated or prevented, either by the development of vaccines or the development of medications such as small molecules that bind to and inhibit coronavirus proteins, and prevent them from multiplying in the human body.SARS-CoV-2 has more than 25 distinct proteins, which can be divided into three distinct classes. One class of proteins are called the non-structural proteins, and these are involved in creating many new copies of the virus and infection of other humans. We therefore decided to work on one of the non-structural proteins, named non-structural protein 10 (nsp10). Although a relatively small protein it activates at least two other non-structural viral proteins (nsp14 and nsp16), without which the virus cannot multiply. By blocking nsp10, we can equally block these two other viral proteins, and the virus ceases to be 'viable'.In this project we propose to build upon our previous work to develop inhibitors that bind to and block the action of nsp10. In the future, these inhibitors could be combined with other drugs that bind to and block other proteins present in SARS-CoV-2, leading to even more potent drug combinations. With this approach, we hope to not only combat SARS-CoV-2 but also closely related novel coronaviruses that may cause new outbreaks in the foreseeable future.