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。大约25%的普通感冒病例是由它们引起的。在过去的20年里，各种冠状病毒爆发代表着严重的威胁，例如中国爆发的SARS，感染了8000人，死亡率约为10%。随后，2012年在沙特阿拉伯和2015年在韩国分别爆发了另一次疫情，迄今为止造成约2500例感染，死亡率为34%。这种新型冠状病毒被命名为中东呼吸综合征，因为它起源于中东。导致当前Covid-19大流行的最新新型冠状病毒名为SARS-CoV-2，已在全球造成5.5亿多人感染和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。很难预测今年冬天及以后我们是否会面临冠状病毒的进一步高峰，也很难预测病毒会发生多大程度的变异，并逃脱疫苗的保护。通过相关病毒从动物传播给人类，未来发生其他冠状病毒疫情的风险也很高。因此，重要的是要研究冠状病毒，以了解它们如何感染人类，以及如何通过开发疫苗或开发药物（如与冠状病毒蛋白结合并抑制它们的小分子）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，可以分为三种不同的类型。一类蛋白质被称为非结构蛋白质，它们参与了病毒的许多新拷贝和对其他人的感染。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质，但它至少激活了另外两种非结构病毒蛋白（nsp14和nsp16），没有它们病毒就无法繁殖。通过阻断nsp10，我们同样可以阻断这另外两种病毒蛋白，病毒就不再是‘活的’了。在这个项目中，我们建议在我们之前的工作基础上开发结合并阻断nsp10作用的抑制剂。在未来，这些抑制剂可以与其他药物结合并阻断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，我们希望不仅可以对抗SARS-CoV-2，还可以对抗密切相关的新型冠状病毒，这些病毒可能在可预见的未来引发新的疫情。

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.