Identification and Design of drugs interfering with the host translational inhibitor nsp1 of SARS-CoV2

Identification and Design of drugs interfering with the host translational inhibitor nsp1 of SARS-CoV2 is a PRACE-supported project led by Prof. Francesco Luigi Gervasio from University College London, United Kingdom. Gervasio's team focusses on the fast mutation rate of the virus as a cause of resistance to antiviral drugs and thus requiring a combined therapy targeting different viral genes. The structures of most SARS-CoV2 proteins have been published, including those of widely studied drug targets, such as the interaction between the viral spike (S) protein and its receptor on the human cell surface. In this project, the scientists propose to target a less studied, but equally important non-structural protein 1 (nsp1). This protein has high identity with SARS-CoV nsp1 of around 86%, which has been determined as a major virulence and pathogenicity factor. Nsp1 inhibits or blocks the cellular innate immune response. It binds to 40S ribosomes to inactivate their translation functions, facilitating efficient viral gene expression in infected cells, and evasion from host immune response. The aim of this project is to explore the druggability of SARS-CoV-2 non-structural protein 1 and the interaction between nsp1 and the ribosome 40S unit with an experimental screening of compound libraries and drug design. The methods used could provide crucial insights into the rational design and screening of compounds for nsp1 and the nsp1:40S ribosome complex. In so doing, the group will pave the way to a complementary strategy for COVID-19 therapeutics. PRACE awarded this project with 6 000 000 core hours on Hawk, hosted by GCS at HLRS, Germany.