The global pandemic COVID-19, caused by the virus SARS-CoV-2, has caused millions of deaths worldwide. In the last few years, scientists have been working hard to develop treatments. While there was a strong focus on vaccines to prevent infection, the development of antiviral drugs to treat the symptoms of severe COVID-19 has been another important strategy. When you are infected with SARS-CoV-2, the virus can penetrate your cells and hijack the body’s natural machinery to replicate and spread the viral infection. There are many viral proteins involved in this replication process, but one of the most important is called the main protease. This has become an important target for antivirals for COVID-19. 

Finding drugs that target a particular protein can be a challenge. One strategy used by scientists involves washing many different molecules over the protein in the laboratory and working out which molecules stick, and which are washed away. The molecules that stick are more likely to block the activity of the protein, compared with the ones that do not stick and are washed away. This process can be done with small molecule drugs quite simply, but it can be tricky with peptides. Peptides are more likely to act as good drugs against large proteins like the main protease, so scientists must employ highly specialised technologies to find peptide drugs. CIPPS Partner Investigator Professor Hiroaki Suga has invented a sophisticated method which allows researchers to wash trillions of different peptide molecules against a protein target to find potential drugs. This technology earned Professor Suga the prestigious Wolf Prize for Chemistry this year and is now being used around the world, including by the Payne research group at our NSW node.  

Dr Jason Johansen-Leete from the Payne group used Professor Suga’s technology to find peptide molecules that block the action of the SARS-CoV-2 main protease. The project was expanded into a significant cross-nodal collaboration with members from our ACT node. Members from the Jackson and Nitsche groups produced the main protease protein, tested the anti-viral activity of the peptide molecules synthesised in the Payne lab and then carefully studied their 3D structures. These structural studies provided important information about the main protease and how the peptides interact with it. Several promising possible drugs were identified which are being optimised by CIPPS CIs and have attracted additional grant funding. Not only has this project led to other exciting publications, such as from our ACT node where the Jackson lab used the discovered molecules to help predict how antiviral drugs would respond to mutations in the SARS-CoV-2 main protease, it has served as an exemplar of how CIPPS can quickly harness the breadth of capabilities from across the Centre and focus efforts towards global science challenges. 

Paper: https://pubs.rsc.org/en/content/articlehtml/2022/sc/d1sc06750h