WIM no. 17 Spring 2020

מכון ויצמן למדע 4–5 S P R I N G 2 0 2 0 Towards a drug against COVID-19 Co-led by Dr. Nir London, global consortium aims to drastically accelerate development of drug A n international initiative led by the Weizmann Institute’s Dr. Nir London has brought together a range of key players in the drug development process—from academia in four countries, to biotech and contract research organizations, to specialized software companies—to accelerate the development of a drug against COVID-19. Dr. London is collaborating with researchers at Oxford University, Memorial Sloan Kettering Cancer Center, University of British Columbia, a California biotech company PostEra, and Enamine, one of the largest chemical vendors in the world, to develop small molecules to target a key SARS-CoV-2 protein that can halt and counteract the virus. The partners have developed the means to characterize the structure of the main protease of SARS-CoV-2—an essential enzyme that is responsible for a key step in the virus life cycle. The researchers have agreed to share all their data openly to avoid bureaucracy and intellectual property considerations. All data is available in real time to the entire research community, inspiring a true open-science global collaboration. Their goal: to target this enzyme’s activity effectively, which would be a key antiviral approach. By ramping up research production in a coordinated effort with contract research organizations (CROs) they are hoping the effort will lead to an effective anti- COVID-19 drug candidate in a matter of months. Dr. London and his team in the Department of Organic Chemistry are experts on drugs that rely on the formation of covalent bonds, and their innovative electrophile-fragment screening platform has been used against various proteins. In the past two weeks, they have applied it to the viral protein (produced and shipped from the UK) and have identified promising initial hits that can potentially serve as starting points for a drug. The Oxford University team and the Diamond Light Source (the UK’s national synchrotron light source science facility), were able, in turn, to determine crystal structures showing how these compounds bind in the protease’s active site. So far, they have identified 78 hits against the SARS-CoV-2 protease, 37 of which are covalent fragments originating from the London lab. Now, they must narrow down the possibilities, which requires the input of medicinal chemists and chemo- informatics and design experts. Crowdsourcing for science To that end, the researchers are hosting an online crowdsourcing challenge to ask medicinal chemists and computer-aided drug design experts around the world to design better molecules based on the available fragments. Close to 2,000 designs have been submitted so far, and the challenge is ongoing. PostEra’s AI-based computational models are used to prioritize chemical synthesis and drug-binding simulations created by software project called Folding@Home would be used to predict binding affinity. Together, these efforts will significantly accelerate the compound-design cycle. Once such promising candidate drugs are identified, Enamine and CROs will be on called to synthesize and test every compound’s safety. g Dr. Nir London Video: Dr. Nir London: The race for a cure Weizmann MAGAZINE