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27 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3 [Next/Last]

Instruments / Technical Area	Publication Details	Published
	Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition Roi Asor , Anna Olerinyova , Sean A. Burnap , Manish S. Kushwah , Fabian Soltermann , Lucas S. P. Rudden , Mario Hensen , Mario Hensen , Snežana Vasiljevic , Juliane Brun , Michelle Hill , Liu Chang , Wanwisa Dejnirattisai , Piyada Supasa , Juthathip Mongkolsapaya , Daming Zhou , David I. Stuart , Gavin R. Screaton , Matteo T. Degiacomi , Nicole Zitzmann , Justin L. P. Benesch , Weston B. Struwe , Philipp Kukura Proceedings Of The National Academy Of Sciences 121 DOI: 10.1073/pnas.2403260121 Open Access Show Abstract ▼ Abstract: Cellular processes are controlled by the thermodynamics of the underlying biomolecular interactions. Frequently, structural investigations use one monomeric binding partner, while ensemble measurements of binding affinities generally yield one affinity representative of a 1:1 interaction, despite the majority of the proteome consisting of oligomeric proteins. For example, viral entry and inhibition in SARS-CoV-2 involve a trimeric spike surface protein, a dimeric angiotensin-converting enzyme 2 (ACE2) cell-surface receptor and dimeric antibodies. Here, we reveal that cooperativity correlates with infectivity and inhibition as opposed to 1:1 binding strength. We show that ACE2 oligomerizes spike more strongly for more infectious variants, while exhibiting weaker 1:1 affinity. Furthermore, we find that antibodies use induced oligomerization both as a primary inhibition mechanism and to enhance the effects of receptor-site blocking. Our results suggest that naive affinity measurements are poor predictors of potency, and introduce an antibody-based inhibition mechanism for oligomeric targets. More generally, they point toward a much broader role of induced oligomerization in controlling biomolecular interactions.	Oct 2024
I03-Macromolecular Crystallography	A structure-function analysis shows SARS-CoV-2 BA.2.86 balances antibody escape and ACE2 affinity Chang Liu , Daming Zhou , Aiste Dijokaite-Guraliuc , Piyada Supasa , Helen M. E. Duyvesteyn , Helen M. Ginn , Muneeswaran Selvaraj , Alexander J. Mentzer , Raksha Das , Thushan I. De Silva , Thomas G. Ritter , Megan Plowright , Thomas A.h. Newman , Lizzie Stafford , Barbara Kronsteiner , Nigel Temperton , Yuan Lui , Martin Fellermeyer , Philip Goulder , Paul Klenerman , Susanna J. Dunachie , Michael I. Barton , Mikhail A. Kutuzov , Omer Dushek , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Reports Medicine 376 DOI: 10.1016/j.xcrm.2024.101553 Diamond Proposal Number(s): [28534, 27009] Open Access Show Abstract ▼ Abstract: BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility.	May 2024
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Emerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection Chang Liu , Raksha Das , Aiste Dijokaite-Guraliuc , Daming Zhou , Alexander J. Mentzer , Piyada Supasa , Muneeswaran Selvaraj , Helen M. E. Duyvesteyn , Thomas G. Ritter , Nigel Temperton , Paul Klenerman , Susanna J. Dunachie , Neil G. Paterson , Mark A. Williams , David R. Hall , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Nature Communications 15 DOI: 10.1038/s41467-024-47393-3 Open Access Show Abstract ▼ Abstract: The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. Twenty eight potent antibodies are isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5, SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of BA.4/5 mAbs culminating in total loss of function with recent XBB.1.5.70 variants containing the so-called ‘FLip’ mutations at positions 455 and 456. Interestingly, activity of some mAbs is regained on the recently reported variant BA.2.86.	Apr 2024
	The SARS-CoV-2 neutralizing antibody response to SD1 and its evasion by BA.2.86 Daming Zhou , Piyada Supasa , Chang Liu , Aiste Dijokaite-Guraliuc , Helen M. E. Duyvesteyn , Muneeswaran Selvaraj , Alexander J. Mentzer , Raksha Das , Wanwisa Dejnirattisai , Nigel Temperton , Paul Klenerman , Susanna J. Dunachie , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Nature Communications 15 DOI: 10.1038/s41467-024-46982-6 Open Access Show Abstract ▼ Abstract: Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to the failure of all mAbs developed for clinical use. Most potent antibodies bind to the receptor binding domain which has become heavily mutated. Here we study responses to a conserved epitope in sub-domain-1 (SD1) of spike which have become more prominent because of mutational escape from antibodies directed to the receptor binding domain. Some SD1 reactive mAbs show potent and broad neutralization of SARS-CoV-2 variants. We structurally map the dominant SD1 epitope and provide a mechanism of action by blocking interaction with ACE2. Mutations in SD1 have not been sustained to date, but one, E554K, leads to escape from mAbs. This mutation has now emerged in several sublineages including BA.2.86, reflecting selection pressure on the virus exerted by the increasing prominence of the anti-SD1 response.	Mar 2024
	Broadly neutralizing antibodies against COVID-19 Daming Zhou , Jingshan Ren , Elizabeth E. Fry , David I. Stuart Current Opinion In Virology 61 DOI: 10.1016/j.coviro.2023.101332 Open Access Show Abstract ▼ Abstract: The COVID-19 pandemic caused by SARS-CoV-2 has led to hundreds of millions of infections and millions of deaths, however, human monoclonal antibodies (mAbs) can be an effective treatment. Since SARS-CoV-2 emerged, a variety of strains have acquired increasing numbers of mutations to gain increased transmissibility and escape from the immune response. Most reported neutralizing human mAbs, including all approved therapeutic ones, have been knocked down or out by these mutations. Broadly neutralizing mAbs are therefore of great value, to treat current and possible future variants. Here, we review four types of neutralizing mAbs against the spike protein with broad potency against previously and currently circulating variants. These mAbs target the receptor-binding domain, the subdomain 1, the stem helix, or the fusion peptide. Understanding how these mAbs retain potency in the face of mutational change could guide future development of therapeutic antibodies and vaccines.	Aug 2023
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Rapid escape of new SARS-CoV-2 Omicron variants from BA.2 directed antibody responses Aiste Dijokaite-Guraliuc , Raksha Das , Daming Zhou , Helen M. Ginn , Chang Liu , Helen M. E. Duyvesteyn , Jiandong Huo , Rungtiwa Nutalai , Piyada Supasa , Muneeswaran Selvaraj , Thushan I. De Silva , Megan Plowright , Thomas A. H. Newman , Hailey Hornsby , Alexander J. Mentzer , Donal Skelly , Thomas G. Ritter , Nigel Temperton , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Cornelius Roemer , Thomas P. Peacock , Neil G. Paterson , Mark A. Williams , David R. Hall , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Reports DOI: 10.1016/j.celrep.2023.112271 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: In November 2021 Omicron BA.1, containing a raft of new spike mutations emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or SARS-CoV-2 infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional RBD amino-acid substitutions compared to BA.2. We describe a panel of 25 potent mAbs generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent mAb binding shifting to 3 clusters, 2 corresponding to early-pandemic binding hotspots. The RBD mutations in recent variants map close to these binding sites and knock out or severely knock down neutralization activity of all but 1 potent mAb. This recent mAb escape corresponds with large falls in neutralization titre of vaccine or BA.1, BA.2 or BA.4/5 immune serum.	Mar 2023
I03-Macromolecular Crystallography	A delicate balance between antibody evasion and ACE2 affinity for Omicron BA.2.75 Jiandong Huo , Aiste Dijokaite-Guraliuc , Chang Liu , Raksha Das , Piyada Supasa , Muneeswaran Selvaraj , Rungtiwa Nutalai , Daming Zhou , Alexander J. Mentzer , Donal Skelly , Thomas G. Ritter , Ali Amini , Sagida Bibi , Sandra Adele , Sile Ann Johnson , Neil G. Paterson , Mark A. Williams , David R. Hall , Megan Plowright , Thomas A. H. Newman , Hailey Hornsby , Thushan I. De Silva , Nigel Temperton , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Andrew J. Pollard , Teresa Lambe , Philip Goulder , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Reports DOI: 10.1016/j.celrep.2022.111903 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: Variants of SARS CoV-2 have caused successive global waves of infection. These variants, with multiple mutations in the spike protein are thought to facilitate escape from natural and vaccine-induced immunity and often increase in the affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor binding domain (RBD). Here we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared to BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection which may explain the rapid spread in India, where BA.2.75 is now the dominant variant. ACE2 affinity appears to be prioritised over greater escape.	Dec 2022
	Switching of receptor binding poses between closely related enteroviruses Daming Zhou , Ling Qin , Helen M. E. Duyvesteyn , Yuguang Zhao , Tzou-Yien Lin , Elizabeth E. Fry , Jingshan Ren , Kuan-Ying A. Huang , David I. Stuart Viruses 14 DOI: 10.3390/v14122625 Open Access Show Abstract ▼ Abstract: Echoviruses, for which there are currently no approved vaccines or drugs, are responsible for a range of human diseases, for example echovirus 11 (E11) is a major cause of serious neonatal morbidity and mortality. Decay-accelerating factor (DAF, also known as CD55) is an attachment receptor for E11. Here, we report the structure of the complex of E11 and the full-length ectodomain of DAF (short consensus repeats, SCRs, 1–4) at 3.1 Å determined by cryo-electron microscopy (cryo-EM). SCRs 3 and 4 of DAF interact with E11 at the southern rim of the canyon via the VP2 EF and VP3 BC loops. We also observe an unexpected interaction between the N-linked glycan (residue 95 of DAF) and the VP2 BC loop of E11. DAF is a receptor for at least 20 enteroviruses and we classify its binding patterns from reported DAF/virus complexes into two distinct positions and orientations, named as E6 and E11 poses. Whilst 60 DAF molecules can attach to the virion in the E6 pose, no more than 30 can attach to E11 due to steric restrictions. Analysis of the distinct modes of interaction and structure and sequence-based phylogenies suggests that the two modes evolved independently, with the E6 mode likely found earlier.	Nov 2022
I03-Macromolecular Crystallography	Antigenic characterization of SARS-CoV-2 Omicron subvariant BA.4.6 Aiste Dijokaite-Guraliuc , Raksha Das , Rungtiwa Nutalai , Daming Zhou , Alexander J. Mentzer , Chang Liu , Piyada Supasa , Susanna J. Dunachie , Teresa Lambe , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , Jiandong Huo , David I. Stuart , Gavin R. Screaton Cell Discovery 8 DOI: 10.1038/s41421-022-00493-0 Diamond Proposal Number(s): [27009] Open Access	Nov 2022
I03-Macromolecular Crystallography	Humoral responses against SARS-CoV-2 Omicron BA.2.11, BA.2.12.1 and BA.2.13 from vaccine and BA.1 serum Jiandong Huo , Aiste Dijokaite-Guraliuc , Rungtiwa Nutalai , Raksha Das , Daming Zhou , Alexander J. Mentzer , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Discovery 8 DOI: 10.1038/s41421-022-00482-3 Diamond Proposal Number(s): [27009] Open Access	Nov 2022

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