An international initiative aims to identify compounds that target a key enzyme in the virus’s life cycle
Dr. Nir London of the Weizmann Institute of Science’s Organic Chemistry Department is co-leading an ambitious project in collaboration with researchers from Oxford University, Memorial Sloan Kettering Cancer Center, University of British Columbia, and a Californian-based biotech company, PostEra. Using a crowdsourcing approach, the researchers will identify small molecules that can bind to and inhibit the viral protein, a protease enzyme known as SARS-CoV-2 that the virus needs to reproduce. The researchers have already characterized the structure of this protease enzyme.
London and his research team had previously developed an advanced method for identifying potential inhibitors; the method is applicable to numerous proteins. They have recently been researching the coronavirus protease protein (using samples sent from the UK) and have already identified promising primary inhibitors that could serve as a starting point for developing drugs against the virus. The Oxford University research group and Diamond Light Source have been able to show how these compounds bind to the active site of the viral enzyme – a finding that can significantly accelerate drug development.
So far the international team has identified close to 80 primary compounds, about half of which were identified using technology developed in London’s lab. To narrow the range of possibilities and focus on those with the highest potential, the scientists are using PostEra’s computational models. These models – which are based on machine-learning – will identify the most synthetically feasible compounds, and even propose compositions for new drug materials.
To distribute the efforts among scientists around the world, the researchers have launched a crowdsourcing challenge, calling upon medicinal chemists and computer-aided drug design experts to design better molecules based on the preliminary findings (https://covid.postera.ai/covid). More than 4,000 proposals have been submitted so far. After identifying potential compounds, contract research organizations then enter the picture to synthesize them and examine their safety.
These experimental compounds will also be sent to research laboratories around the world – including the Weizmann Institute of Science – where their activity against the coronavirus protease enzyme will be tested. Subsequently, the promising compounds will be tested on virus samples isolated from patients, and several will then be developed into potential drug candidates. To avoid delays, the researchers have agreed to share all their data openly. The researchers hope that collaborating with clinical research companies will hasten the development of a potential coronavirus cure. The current goal is to reach pre-clinical animal testing within half a year.
Dr. Nir London’s research is supported by the Dr. Barry Sherman Institute for Medicinal Chemistry; the Honey and Dr. Barry Sherman Lab; the Moross Integrated Cancer Center; the Helen and Martin Kimmel Center for Molecular Design; the Rising Tide Foundation; the Joel and Mady Dukler Fund for Cancer Research; the Estate of Emile Mimran; Virgin JustGiving; Nelson P. Sirotsky; and Weizmann UK. Dr. London is the incumbent of the Alan and Laraine Fischer Career Development Chair.