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

使用基于结构的药物设计对针对 SARS-CoV-2 非结构蛋白 10 的片段命中进行命中到先导优化

• 批准号: MR/X013995/1
• 负责人: Frank Kozielski
• 金额: $ 69.37万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX013995%2F1
• 关键词: Hit; lead; optimisation; fragment; hits

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.

冠状病毒可能已经困扰人类几个世纪了。他们负责大约25%的所有普通感冒病例。在过去的20年里，已经发生了各种冠状病毒爆发，代表了严重的威胁，例如中国的SARS爆发，有8000人感染，死亡率约为100%。百分之十随后，2012年在沙特阿拉伯和2015年在韩国发生了另一次疫情，造成约1000人死亡。到目前为止有2500例感染，死亡率为34%。这种新型冠状病毒被命名为MERS，因为它起源于中东。最近的新型冠状病毒，命名为SARS-CoV-2，导致目前的Covid-19大流行，已造成全球超过5.5亿人感染，超过620万人死亡。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进一步的冠状病毒高峰，以及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到人类，未来将发生更多冠状病毒爆发的风险也很高。因此，研究冠状病毒以了解它们如何感染人类以及如何治疗或预防这些感染是很重要的，无论是通过开发疫苗还是开发药物，如结合并抑制冠状病毒蛋白的小分子，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，可分为三个不同的类别。其中一类蛋白质被称为非结构蛋白质，它们参与了病毒的复制和感染。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（nsp 10）。虽然它是一种相对较小的蛋白质，但它至少激活两种其他非结构性病毒蛋白（nsp 14和nsp 16），没有它们病毒就不能繁殖。通过阻断nsp 10，我们同样可以阻断这两种其他病毒蛋白，病毒不再是“活的”。在这个项目中，我们建议在我们以前的工作基础上开发抑制剂，结合并阻断nsp 10的作用。在未来，这些抑制剂可以与其他药物结合，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，我们希望不仅能对抗SARS-CoV-2，还能对抗可能在可预见的未来导致新疫情的密切相关的新型冠状病毒。