New tools for the fight against COVID-19 July 5, 2021 Professor Vicky Cowling Seven new papers have been published this month in The Biochemical Journal, representing a major collaboration between multiple groups at the Francis Crick Institute in London, University College London and The University of Dundee. Led by John Diffley at the Francis Crick Institute, with important contributions in Dundee from the groups of Yogesh Kulathu and Karim Labib in the MRC Protein Phosphorylation and Ubiquitylation Unit, together with Vicky Cowling in the division of Gene Regulation and Expression, the idea was to ‘repurpose’ existing drugs to combat the SARS-CoV-2 virus that causes COVID19. Existing drugs and other chemical compounds were screened to search for ones that might fortuitously interfere with the molecular machinery of SARS-CoV-2, at the same time as inhibiting the cellular machinery to which each drug or small chemical compound was originally developed. So far, the main approach to combating the COVID19 pandemic has been via the development of vaccines, which prevent severe disease by interfering with entry of SARS-CoV-2 into human cells. The vaccines bind tightly to the virus’s ‘Spike protein’ on the surface of the viral particle, thereby preventing the spike protein from engaging the surface of the host cell (a step that normally triggers viral entry). Multiple vaccines to the SARS-CoV-2 spike protein have been developed in record time, but affordable treatments are still needed for those people who develop the disease, particularly those who are not yet vaccinated. In addition, it is possible that mutations in the spike protein could lead to variants of the virus that are resistant to current vaccines. For these reasons, it is also important to develop treatments for COVID19 that are based on drugs that inhibit the proliferation of the virus once it has gained entry to our cells. The virus forces our cells to produce a series of molecular machines or enzymes, which are essential for viral replication but are not required for human cell biology. These enzymes have been slow to change during viral evolution, suggesting that drug resistant viruses might be slow to emerge, in contrast to the rapid acquisition of mutations in the viral spike protein. Moreover, drugs that inhibit the enzymes of SARS-CoV-2 might also be effective against other related coronaviruses. Professor Ron Hay Each of the seven new papers describes a screen for small molecules that inhibit one of the essential enzymes of SARS-CoV-2. The project was only possible by bringing together expertise from multiple labs in several leading institutions. Three of the studies involved important contributions from the groups of Yogesh Kulathu (Lee Armstrong, Sven Lange), Karim Labib (Tom Deegan & Ryo Fujisawa) and Vicky Cowling. These papers describe the successful identification of chemical inhibitors for the seven enzymes from SARS-CoV-2. Some of these inhibitors are already in clinical use to treat other diseases and could potentially be repurposed for COVID19, whereas others might be leads for future drug development. Considered together, the newly characterised inhibitors represent a ‘chemical toolbox’ with which to study the biology of SARS-CoV-2 and develop new treatments. The project also illustrates the potential for developing new anti-viral drugs that might have broad efficacy across groups of viruses. Such drugs would not only complement the development of vaccines but might also provide a very important ‘first line of defence’ to new viral threats, whilst new vaccines are still being developed. More details about this work can be found in the newly published set of seven papers, together with a commentary from Professor Ron Hay in the division of Gene Regulation and Expression at the University of Dundee.