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168 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses Wanwisa Dejnirattisai , Jiandong Huo , Daming Zhou , Jiří Zahradník , Piyada Supasa , Chang Liu , Helen M. E. Duyvesteyn , Helen M. Ginn , Alexander J. Mentzer , Aekkachai Tuekprakhon , Rungtiwa Nutalai , Beibei Wang , Aiste Dijokaite , Suman Khan , Ori Avinoam , Mohammad Bahar , Donal Skelly , Sandra Adele , Sile Ann Johnson , Ali Amini , Thomas Ritter , Chris Mason , Christina Dold , Daniel Pan , Sara Assadi , Adam Bellass , Nikki Omo-Dare , David Koeckerling , Amy Flaxman , Daniel Jenkin , Parvinder K. Aley , Merryn Voysey , Sue Ann Costa Clemens , Felipe Gomes Naveca , Valdinete Nascimento , Fernanda Nascimento , Cristiano Fernandes Da Costa , Paola Cristina Resende , Alex Pauvolid-Correa , Marilda M. Siqueira , Vicky Baillie , Natali Serafin , Gaurav Kwatra , Kelly Da Silva , Shabir A. Madhi , Marta C. Nunes , Tariq Malik , Peter J. M. Openshaw , J. Kenneth Baillie , Malcolm G. Semple , Alain R. Townsend , Kuan-Ying A. Huang , Tiong Kit Tan , Miles W. Carroll , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Bede Constantinides , Hermione Webster , Derrick Crook , Andrew J. Pollard , Teresa Lambe , Neil G. Paterson , Mark A. Williams , David R. Hall , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , Gideon Schreiber , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.12.046 Diamond Proposal Number(s): [27009] Show Abstract ▼ Abstract: On the 24th November 2021 the sequence of a new SARS CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses.	Jan 2022
I24-Microfocus Macromolecular Crystallography	Bacteriophage PRD1 as a nanoscaffold for drug loading Helen M. E. Duyvesteyn , Isaac Santos-Perez , Francesca Peccati , Ane Martinez-Castillo , Thomas S. Walter , David Reguera , Felix M. Goñi , Gonzalo Jiménez-Osés , Hanna M. Oksanen , David I. Stuart , Nicola G. A. Abrescia Nanoscale 156 DOI: 10.1039/D1NR04153C Diamond Proposal Number(s): [14744] Open Access Show Abstract ▼ Abstract: Viruses are very attractive biomaterials owing to their capability as nanocarriers of genetic material. Efforts have been made to functionalize self-assembling viral protein capsids on their exterior or interior to selectively take up different payloads. PRD1 is a double-stranded DNA bacteriophage comprising an icosahedral protein outer capsid and an inner lipidic vesicle. Here, we report the three-dimensional structure of PRD1 in complex with the antipsychotic drug chlorpromazine (CPZ) by cryo-electron microscopy. We show that the jellyrolls of the viral major capsid protein P3, protruding outwards from the capsid shell, serve as scaffolds for loading heterocyclic CPZ molecules. Additional X-ray studies and molecular dynamics simulations show the binding modes and organization of CPZ molecules when complexed with P3 only and onto the virion surface. Collectively, we provide a proof of concept for the possible use of the lattice-like organisation and the quasi-symmetric morphology of virus capsomers for loading heterocyclic drugs with defined properties.	Dec 2021
	Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum Wanwisa Dejnirattisai , Robert H. Shaw , Piyada Supasa , Chang Liu , Arabella S. V. Stuart , Andrew J Pollard , Xinxue Liu , Teresa Lambe , Derrick Crook , Dave I. Stuart , Juthathip Mongkolsapaya , Jonathan S. Nguyen-Van-Tam , Matthew D. Snape , Gavin R. Screaton The Lancet DOI: 10.1016/S0140-6736(21)02844-0	Dec 2021
I03-Macromolecular Crystallography	Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2 Kuan-Ying A. Huang , Daming Zhou , Tiong Kit Tan , Charles Chen , Helen M. E. Duyvesteyn , Yuguang Zhao , Helen M. Ginn , Ling Qin , Pramila Rijal , Lisa Schimanski , Robert Donat , Adam Harding , Javier Gilbert-Jaramillo , William James , Julia A. Tree , Karen Buttigieg , Miles Carroll , Sue Charlton , Chia-En Lien , Meei-Yun Lin , Cheng-Pin Chen , Shu-Hsing Cheng , Xiaorui Chen , Tzou-Yien Lin , Elizabeth E. Fry , Jingshan Ren , Che Ma , Alain R. Townsend , David I. Stuart Theranostics DOI: 10.7150/thno.65563 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: Background: Administration of potent anti-receptor-binding domain (RBD) monoclonal antibodies has been shown to curtail viral shedding and reduce hospitalization in patients with SARS-CoV-2 infection. However, the structure-function analysis of potent human anti-RBD monoclonal antibodies and its links to the formulation of antibody cocktails remains largely elusive. Methods: Previously, we isolated a panel of neutralizing anti-RBD monoclonal antibodies from convalescent patients and showed their neutralization efficacy in vitro. Here, we elucidate the mechanism of action of antibodies and dissect antibodies at the epitope level, which leads to a formation of a potent antibody cocktail. Results: We found that representative antibodies which target non-overlapping epitopes are effective against wild type virus and recently emerging variants of concern, whilst being encoded by antibody genes with few somatic mutations. Neutralization is associated with the inhibition of binding of viral RBD to ACE2 and possibly of the subsequent fusion process. Structural analysis of representative antibodies, by cryo-electron microscopy and crystallography, reveals that they have some unique aspects that are of potential value while sharing some features in common with previously reported neutralizing monoclonal antibodies. For instance, one has a common VH 3-53 public variable region yet is unusually resilient to mutation at residue 501 of the RBD. We evaluate the in vivo efficacy of an antibody cocktail consisting of two potent non-competing anti-RBD antibodies in a Syrian hamster model. We demonstrate that the cocktail prevents weight loss, reduces lung viral load and attenuates pulmonary inflammation in hamsters in both prophylactic and therapeutic settings. Although neutralization of one of these antibodies is abrogated by the mutations of variant B.1.351, it is also possible to produce a bi-valent cocktail of antibodies both of which are resilient to variants B.1.1.7, B.1.351 and B.1.617.2. Conclusions: These findings support the up-to-date and rational design of an anti-RBD antibody cocktail as a therapeutic candidate against COVID-19.	Nov 2021
I03-Macromolecular Crystallography	The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants Chang Liu , Daming Zhou , Rungtiwa Nutalai , Helen M. E. Duyvesteyn , Aekkachai Tuekprakhon , Helen M. Ginn , Wanwisa Dejnirattisai , Piyada Supasa , Alexander J. Mentzer , Beibei Wang , James Brett Case , Yuguang Zhao , Donal T. Skelly , Rita E. Chen , Sile Ann Johnson , Thomas G. Ritter , Chris Mason , Tariq Malik , Nigel Temperton , Neil G. Paterson , Mark A. Williams , David R. Hall , Daniel K. Clare , Andrew Howe , Philip J. R. Goulder , Elizabeth E. Fry , Michael S. Diamond , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Host & Microbe DOI: 10.1016/j.chom.2021.11.013 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1 and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor binding domain (RBD). Two of these RBD-binding mAbs recognise a neutralizing epitope conserved between SARS-CoV-1 and -2, whilst 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.	Nov 2021
I03-Macromolecular Crystallography Krios I-Titan Krios I at Diamond	Mapping antibody recognition of SARS-CoV-2 spike protein Jingshan Ren , David I. Stuart Diamond Proposal Number(s): [27009, 26983] Show Abstract ▼ Abstract: The COVID-19 vaccines currently in use in Europe and the USA aim to generate antibodies against the virus spike. We need to know where these antibodies bind and how they neutralise the virus. Viruses mutate to escape antibody binding, and changes to the spike structure can stop antibody attachment. An international team of researchers identified 377 human monoclonal antibodies (mAbs) from recovered SARS-CoV-2 patients that recognised the virus spike. They used cryo-electron microscopy (cryo-EM) at the Electron Bio-Imaging Centre (eBIC) and Macromolecular Crystallography (MX) on beamline I03 at Diamond Light Source to investigate the complex structures of the SARS-CoV-2 spike or the receptor binding domain (RBD) with the antibody Fabs (a region on an antibody that binds to antigens). The team determined the structures of 11 spike/Fab complexes by cryo-EM and 18 RBD/fab complexes by crystallography. Using a combination of structural methods, and a novel computational algorithm utilising competition bio-layer interferometry data, they localised binding epitopes of 80 on the surface of the RBD. Three of the potent neutralising mAbs are glycosylated, and the glycans contribute to neutralisation. Their results identify the precise binding sites on the spike and their detailed interactions. This information can guide combinations for antibody cocktail therapy. More potent neutralising monoclonal antibodies (mABs) can be designed through structural analysis. Understanding how the binding of these antibodies is affected in variant viruses is helpful in understanding how we might design next- generation vaccines. The project involved many groups working closely together, and success in such a difficult time was only possible due to tremendous support and collaboration with eBIC, the Oxford Particle Imaging Centre (OPIC) and I03.	Jul 2021
	Site-specific steric control of SARS-COV-2 spike glycosylation Joel D. Allen , Himanshi Chawla , Firdaus Samsudin , Lorena Zuzic , Aishwary Tukaram Shivgan , Yasunori Watanabe , Wan-Ting He , Sean Callaghan , Ge Song , Peter Yong , Philip J. M. Brouwer , Yutong Song , Yongfei Cai , Helen M. E. Duyvesteyn , Tomas Malinauskas , Joeri Kint , Paco Pino , Maria J. Wurm , Martin Frank , Bing Chen , David I. Stuart , Rogier W. Sanders , Raiees Andrabi , Dennis R. Burton , Sai Li , Peter J. Bond , Max Crispin Biochemistry DOI: 10.1021/acs.biochem.1c00279 Open Access Show Abstract ▼ Abstract: A central tenet in the design of vaccines is the display of native-like antigens in the elicitation of protective immunity. The abundance of N-linked glycans across the SARS-CoV-2 spike protein is a potential source of heterogeneity among the many different vaccine candidates under investigation. Here, we investigate the glycosylation of recombinant SARS-CoV-2 spike proteins from five different laboratories and compare them against S protein from infectious virus, cultured in Vero cells. We find patterns that are conserved across all samples, and this can be associated with site-specific stalling of glycan maturation that acts as a highly sensitive reporter of protein structure. Molecular dynamics simulations of a fully glycosylated spike support a model of steric restrictions that shape enzymatic processing of the glycans. These results suggest that recombinant spike-based SARS-CoV-2 immunogen glycosylation reproducibly recapitulates signatures of viral glycosylation.	Jul 2021
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19 Martin A. Redhead , C. David Owen , Lennart Brewitz , Amelia H. Collette , Petra Lukacik , Claire Strain-Damerell , Sean W. Robinson , Patrick M. Collins , Philipp Schäfer , Mark Swindells , Chris J. Radoux , Iva Navratilova Hopkins , Daren Fearon , Alice Douangamath , Frank Von Delft , Tika R. Malla , Laura Vangeel , Thomas Vercruysse , Jan Thibaut , Pieter Leyssen , Tu-Trinh Nguyen , Mitchell Hull , Anthony Tumber , David J. Hallett , Christopher J. Schofield , David I. Stuart , Andrew L. Hopkins , Martin A. Walsh Scientific Reports 11 DOI: 10.1038/s41598-021-92416-4 Open Access Show Abstract ▼ Abstract: Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (Mpro) and the papain-like protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.	Jun 2021
I03-Macromolecular Crystallography	Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum Chang Liu , Helen M. Ginn , Wanwisa Dejnirattisai , Piyada Supasa , Beibei Wang , Aekkachai Tuekprakhon , Rungtiwa Nutalai , Daming Zhou , Alexander J. Mentzer , Yuguang Zhao , Helen M. E. Duyvesteyn , César López-Camacho , Jose Slon-Campos , Thomas Walter , Donal Skelly , Sile Ann Johnson , Thomas G. Ritter , Chris Mason , Sue Ann Costa Clemens , Felipe Gomes Naveca , Valdinete Nascimento , Fernanda Nascimento , Cristiano Fernandes Da Costa , Paola Cristina Resende , Alex Pauvolid-Correa , Marilda M. Siqueira , Christina Dold , Nigel Temperton , Tao Dong , Andrew J. Pollard , Julian C. Knight , Derrick Crook , Teresa Lambe , Elizabeth Clutterbuck , Sagida Bibi , Amy Flaxman , Mustapha Bittaye , Sandra Belij-Rammerstorfer , Sarah C. Gilbert , Tariq Malik , Miles W. Carroll , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Vicky Baillie , Natali Serafin , Zanele Ditse , Kelly Da Silva , Neil G. Paterson , Mark A. Williams , David R. Hall , Shabir Madhi , Marta C. Nunes , Philip Goulder , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.06.020 Diamond Proposal Number(s): [27009] Show Abstract ▼ Abstract: SARS-CoV-2 has undergone progressive change with variants conferring advantage rapidly becoming dominant lineages e.g. B.1.617. With apparent increased transmissibility variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the UK. Here we study the ability of monoclonal antibodies, convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2 and complement this with structural analyses of Fab/RBD complexes and map the antigenic space of current variants. Neutralization of both viruses is reduced when compared with ancestral Wuhan related strains but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2 suggesting that individuals previously infected by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insight for immunisation policy with future variant vaccines in non-immune populations.	Jun 2021
I03-Macromolecular Crystallography	Antibody evasion by the P.1 strain of SARS-CoV-2 Wanwisa Dejnirattisai , Daming Zhou , Piyada Supasa , Chang Liu , Alexander J. Mentzer , Helen M. Ginn , Yuguang Zhao , Helen M. E. Duyvesteyn , Aekkachai Tuekprakhon , Rungtiwa Nutalai , Beibei Wang , Guido Paesen , César López-Camacho , Jose Slon-Campos , Thomas S. Walter , Donal Skelly , Sue Ann Costa Clemens , Felipe Gomes Naveca , Valdinete Nascimento , Fernanda Nascimento , Cristiano Fernandes Da Costa , Paola C. Resende , Alex Pauvolid-Correa , Marilda M. Siqueira , Christina Dold , Robert Levin , Tao Dong , Andrew J. Pollard , Julian C. Knight , Derrick Crook , Teresa Lambe , Elizabeth Clutterbuck , Sagida Bibi , Amy Flaxman , Mustapha Bittaye , Sandra Belij-Rammerstorfer , Sarah Gilbert , Miles W. Carroll , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Neil G. Paterson , Mark A. Williams , David R. Hall , Ruben J. G. Hulswit , Thomas A. Bowden , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.03.055 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations: P.1 from Brazil, B.1.351 from South Africa and B.1.1.7 from the UK (12, 10 and 9 changes in the spike respectively). All have mutations in the ACE2 binding site with P.1 and B.1.351 having a virtually identical triplet: E484K, K417N/T and N501Y, which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine induced antibody responses than B.1.351 suggesting that changes outside the RBD impact neutralisation. Monoclonal antibody 222 neutralises all three variants despite interacting with two of the ACE2 binding site mutations, we explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.	Mar 2021

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