Diamond Concise Annual Review 2020/21

8 9 D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 2 0 / 2 1 By the end of March 2020, a massive fragment screening effort to develop an antiviral targeting the SARS-CoV-2 main protease had identified potential ways to rapidly design improved and more potent compounds in the fight against COVID-19. The team combined mass spectrometry with Diamond's XChem facility to rapidly identify lead compounds for drug development to treat the disease.  Six SARS-CoV-2 proteins have now been subjected to fragment screening at Diamond. One of these protein drug targets forms part of another SARS-CoV-2 protein essential for viral replication, and was targeted by a collaboration of researchers.Theyfocusedonaspecificproteindomain,knownasthemacrodomain, that is an attractive target for drug discovery. Previous research has shown that without a functioning macrodomain, coronaviruses are unable to replicate in human cells. This work is thus foundational for preparing for future pandemics. Developing new therapies Critically ill patients with COVID-19 given a transfusion of serum from convalesced individuals, who have antibodies against the virus, greatly improves their chances of survival. However, a lab-based product that can be made on demand would have considerable advantages and could be used earlier in the disease where it is likely to be more effective. In July 2020, researchers showed that antibodies derived from llamas could neutralise the SARS-CoV-2 virus in lab tests. Using advanced imaging at Diamond and Oxford, the team also showed that the antibodies bind to the spike protein in a new and different way to other antibodies already discovered. These antibodies – known as nanobodies due to their small size – could eventually be developed as a treatment for patients with severe COVID-19. Screening existing drugs as potential COVID-19 treatments Developing new drugs is a long and costly process. However, more than 15,000 compounds have been approved and extensively tested for human safety in clinical trials or regulatory pre-clinical safe studies. In March 2020, Diamond launched a new initiative with Exscientia and Scripps Research to accelerate the path to clinical trials for potential COVID-19 antiviral treatments and applied biosensor platforms to screen a number of clinical drug molecules against several viral drug targets of SARS-CoV-2. Beyond the science Diamond is a world-class science facility, but is also a community. In March 2020, Diamond’s staff joined an initiative to create stocks of 3D printed visors for local health workers. A team used 20 3D printers to make over 1,000 visors a week. Visor parts were brought to Diamond for sterilisation and packing before distribution. By June, the effort had produced more than 10,000 visors, filling the gap until commercial production could meet demand. Diamond started offering PCR tests for staff working on-site to quickly identify any infected individuals and trace their contacts, preventing COVID-19 from spreading. This and other protective measures gave staff the confidence that working at Diamond was as safe as possible. Lateral flow tests were also provided for visitors. Diamond was able to run for four or five days each week during the first year of the pandemic, although not all of the beamlines were operational. Moving our programme of public events online has allowed us to continue engaging with the public, in a year in which the contribution of science to humanity’s future has never been more prominent. Rising to the Challenge of COVID-19 I n March 2020 the urgent priorities for researchers were to learn more about SARS-CoV-2, the virus that causes COVID-19. A structural understanding of the virus was critical for developing vaccines and treatments, and Diamond Light Source's facilities would become crucial tools for researchers. Over the past few years, Diamond has been developing technology and software for highly-automated, high-throughput beamlines. This allows more experiments to be run remotely, with users sending samples to Diamond rather than visiting. This became Diamond’s standard way of working during the pandemic, with beamtime reserved for research related to COVID-19. Diamond allocated beamtime via a new COVID-19 specific rapid access route, andmore than 60 projects have benefited from expedited access in the last year. The many COVID-19 related research projects are a great demonstration of the powerful synergy between Diamond and its neighbouring research institutes. The COVID-19 research taking place at Diamond can be loosely grouped into five major strands. Understanding the virus structure and function By August 2020, an international team of researchers had discovered a new site on the SARS-CoV-2 virus that could be neutralised by a specific antibody. Using the Electron Bio-Imaging Centre (eBIC) at Diamond, and working with a group at a hospital inTaiwan, the team identified antibodies froma convalescent patient with potential for a drug target. In November 2020, a research group led by Peijun Zhang, Director of eBIC, published the results of their investigation of the virus replication and showed the profound cell changes caused by infection. This enabled modelling of genome replication, virus assembly and egress pathways, which was critically important to help combat COVID-19. Diamond then created a detailed scientific animation showing how the virus infection mechanism works at the cellular level. This was the first time the virus had been depicted in this way, showing in detail how the virus infection mechanism operates. In March 2021, a study reported results from a large cohort of COVID-19 patients. X-ray crystallography and cryogenic electron microscopy (cryo-EM) at Diamond allowed an international research team to visualise how antibodies interact with and neutralise the virus.The study provided a basis for understanding the effect on antibody neutralisation of mutations in several of the variant viruses which are now a cause for concern around the world. Vaccine design In April 2021, eBIC published the first images of cells exposed to the Oxford- AstraZeneca vaccine and supported the use of modified adenovirus in the vaccine as a leading platform to combat COVID-19. The challenge now is to stay ahead of themutations, and the race is on to understand the consequences of these changes and to develop new vaccine constructs tailored to the variants. Ongoing studies are providing valuable new information on how previously infected or vaccinated individuals respond to new variants and antibodies. New drug development To defeat the virus, a combination of vaccines and treatments will be needed for people who become infected. An attractive drug target is the so-called main protease of SARS-CoV-2.This protein is essential for viral replication.Work initiated in theWalsh Group at Diamond in January 2020, in collaboration with the von Delft Group, inspired a novel crowd sourcing initiative led by PostEra Inc – the COVID Moonshot, established to develop an effective antiviral more rapidly than ever before. The project crowdsourced designs of new inhibitors from chemists around the world who were using the Diamond ‘fragment’data, which had been released in real-time to enable worldwide collaboration and rapid progress. Promising compounds were synthesised and tested for antiviral activity and toxicity. This is ongoing drug discovery work.