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

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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.