Diamond 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 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 partnership with the University of Oxford) can screen up to 1,000 compounds in less than a week. 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 forward to rapidly design improved and more potent compounds in the fight against COVID-19 8 .The project was led by Martin Walsh, Deputy Life Sciences Director at Diamond, Frank von Delft, Professor of Structural Chemical Biology at the University of Oxford and Principal Beamline Scientist of I04-1/XChem and Nir London, Assistant Professor at the Weizmann Institute Israel.  The team combined mass spectrometry with the XChem facility to rapidly identify lead compounds for drug development to treat COVID-19.  Six SARS-CoV-2 proteins have now been subjected to fragment screening at Diamond in collaboration with internal and external groups. One of these protein drug targets forms part of another SARS-CoV-2 protein essential for viral replication.InthiscaseresearchersatXChem,incollaborationwiththeUniversity of Oxford and the QCRG Structural Biology Consortium at the University of California San Francisco, targeted one of the domains of the largest SARS-CoV-2 proteins named non-structural protein 3 (Nsp3) 9 . Their research, published in Science Advances , focused on a specific protein domain of Nsp3 known as the macrodomain, which is an attractive target for drug discovery as previous research has shown that without a functioningmacrodomain, coronaviruses are unable to replicate in human cells. This work is thus foundational for preparing for future pandemics. Developing new therapies When patients critically ill with COVID-19 are given a transfusion of serum from convalesced individuals, which contains human antibodies against the virus, this has been shown to greatly improve their chances of survival. This process, known as passive immunisation, has been used for over 100 years. However, it is not straightforward to identify individuals with the right antibodies and to give such a blood product safely. 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, a collaboration with researchers from Diamond, the Rosalind Franklin Institute, the University of Oxford and Public Health England (PHE) showed that antibodies derived from llamas could neutralise the SARS-CoV-2 virus in lab tests 10 . Using advanced imaging with X-rays and electrons at DiamondandOxford,theteamalsoshowedthattheantibodiesbindtothespike 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. Using Diamond’s research on COVID-19 and research facilities, Exscientia would screennearlyeveryknown,approvedand investigationaldrugagainstCOVID-19 drug targets to search for rapid treatments. Using a collection of clinical drug molecules funded by the Bill & Melinda Gates Foundation and shipped from Scripps Research in California, Exscientia applied biosensor platforms to screen them against several viral drug targets of SARS-CoV-2. Beyond the science Diamond is a world-class research centre, but it is also a community of staff and users. In March 2020, when the worldwide demand for PPE outstripped supply, Diamond’s staff joined forces with Covid Print Oxford, an initiative to create stocks of 3D printed visors for local health workers. They created a fully operational 3D printing farm in one of Diamond’s labs, and a team of engineers, technicians and scientists used 20 3D printers to make over 1,000 visors a week. The collective brought all the visor parts to Diamond for sterilisation and packing before distributing them to health and care workers and schools. By June 2020, the effort had producedmore than 10,000 visors, filling the gap until commercial production could meet demand. In June, Diamond also provided more capacity for life sciences research beyond COVID-19, as sadly other diseases do not take a break during a global crisis. After consultations about best practise with other leading institutions, including the Francis Crick Institute in London, Diamond started offering PCR tests for staff working on-site.With results available the same day, this meant it was possible to quickly identify any infected individuals and trace their contacts, preventing COVID-19 from spreading inside Diamond. Combined with other measures (including provision of PPE and hand sanitiser stations), this gave staff the confidence that working at Diamond was as safe as possible. Diamond also provides lateral flow tests for visiting contractors and users. With a responsive and comprehensive operational response, Diamond has been able to run around the clock for four to five days each week during the first year of the pandemic, although not all of the beamlines could be operational. And by moving its programme of public events online, Diamond was able to engage with 6,000 people and continue educating the public, in a year in which the contribution of science to humanity’s future has never been more prominent. References: 1. Zhou D. et al. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. Nat. Struct. Mol. Biol. 27 , 950–958 (2020). DOI: 10.1038/s41594-020-0480-y 2. Mendonça L. et al. SARS-CoV-2 Assembly and Egress Pathway Revealed by Correlative Multi-modal Multi-scale Cryo-imaging. bioRxiv 2020.11.05.370239 (2020). DOI: 10.1101/2020.11.05.370239 Graphic depiction of the process of creating protein spikes on cells. Diamond supported the local community by producing 3D printed visors for health workers. 3. Dejnirattisai W. et al . The Antigenic Anatomy of SARS-CoV-2 Receptor Binding Domain. Cell 184 , (2021). DOI: 10.1016/j.cell.2021.02.032 4. Watanabe Y. et al. Native-like SARS-CoV-2 Spike Glycoprotein Expressed by ChAdOx1 nCoV-19/AZD1222 Vaccine. ACS Cent. Sci. 7 , 594–602 (2021). DOI: 10.1021/acscentsci.1c00080 5. Supasa P. et al. Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera. Cell 184 , 2201-2211.e7 (2021). DOI: 10.1016/j.cell.2021.02.033 6. Zhou D. et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell 184 , 2348-2361.e6 (2021). DOI: 10.1016/j.cell.2021.02.037 7. Dejnirattisai W. et al. Antibody evasion by the P.1 strain of SARS-CoV-2. Cell (2021). DOI: 10.1016/j.cell.2021.03.055 8. Douangamath A. et al. Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease. Nat. Commun. 11 , 5047 (2020). DOI: 10.1038/s41467-020-18709-w 9. Schuller M. et al. Fragment binding to the Nsp3 macrodomain of SARS- CoV-2 identified through crystallographic screening and computational docking. Sci. Adv. 7 , eabf8711 (2021). DOI: 10.1126/sciadv.abf8711 10.Huo J. et al. Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2. Nat. Struct. Mol. Biol. 27 , 846–854 (2020). DOI: 10.1038/s41594-020-0469-6 Surface representation of SARS CoV-2 Mpro protein with fragment hits from XChem platform bound in active site (green).