When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy DOI
Emma Goulard Coderc de Lacam, Marharyta Blazhynska, Haochuan Chen

и другие.

Journal of Chemical Theory and Computation, Год журнала: 2022, Номер 18(10), С. 5890 - 5900

Опубликована: Сен. 15, 2022

Accurate determination of binding free energy is pivotal for the study many biological processes and has been applied in a number theoretical investigations to compare affinity severe acute respiratory syndrome coronavirus 2 variants toward host cell. Diversity these challenges development effective general therapies, their transmissibility relying either on an increased dedicated human receptor, angiotensin-converting enzyme (ACE2), or escaping immune response. Now that robust structural data are available, we have determined with utmost accuracy standard receptor-binding domain most widespread variants, namely, Alpha, Beta, Delta, Omicron BA.2, as well wild type (WT) complex ACE2 antibodies, S2E12 H11-D4, using rigorous framework combines molecular dynamics potential-of-mean-force calculations. Our results show appropriate starting structure crucial ensure reproduction affinity, allowing be compared. They also emphasize necessity apply relevant methodology, bereft any shortcut, account all contributions energy. estimates affinities support view while Alpha Beta lean cell, Delta BA.2 choose escape. Moreover, antibody, already known active against WT (Starr et al., 2021; Mlcochova 2021), proved equally variant. In stark contrast, H11-D4 retains low compared latter. Assuming information, methodology employed herein successfully addresses challenging protein-protein problem context disease 2019 offering promising perspectives predictive studies ever-emerging variants.

Язык: Английский

An updated atlas of antibody evasion by SARS-CoV-2 Omicron sub-variants including BQ.1.1 and XBB DOI Creative Commons

Qingwen He,

Lili Wu, Zepeng Xu

и другие.

Cell Reports Medicine, Год журнала: 2023, Номер 4(4), С. 100991 - 100991

Опубликована: Март 21, 2023

Emerging Omicron sub-variants are causing global concerns, and their immune evasion should be monitored continuously. We previously evaluated the escape of BA.1, BA.1.1, BA.2, BA.3 from an atlas 50 monoclonal antibodies (mAbs), covering seven epitope classes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD). Here, we update totally 77 mAbs against emerging including BQ.1.1 XBB find that BA.4/5, BQ.1.1, display further evasion. Besides, investigation into correlation binding neutralization reveals important role antigenic conformation in mAb functioning. Moreover, complex structures BA.2 RBD/BD-604/S304 BA.4/5 RBD/BD-604/S304/S309 elucidate molecular mechanism antibody by these sub-variants. By focusing on identified broadly potent mAbs, a general hotspot RBD, which could guide design vaccines calls for new broad-spectrum countermeasures COVID-19.

Язык: Английский

Процитировано

67
Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape DOI Creative Commons
Leander Witte, Viren A. Baharani, Fabian Schmidt

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 19, 2023

Waves of SARS-CoV-2 infection have resulted from the emergence viral variants with neutralizing antibody resistance mutations. Simultaneously, repeated antigen exposure has generated affinity matured B cells, producing broadly receptor binding domain (RBD)-specific antibodies activity against emergent variants. To determine how might escape these antibodies, we subjected chimeric viruses encoding spike proteins ancestral, BA.1 or BA.2 to selection by 40 antibodies. We identify numerous examples epistasis, whereby in vitro selected and naturally occurring substitutions RBD epitopes that do not confer Wuhan-Hu-1 spike, so spikes. As few as 2 3 BA.5 nearly all substantial plasma most individuals. Thus, epistasis facilitates acquisition remained effective early omicron

Язык: Английский

Процитировано

60
Targetable elements in SARS-CoV-2 S2 subunit for the design of pan-coronavirus fusion inhibitors and vaccines DOI Creative Commons

Liyan Guo,

Sheng Lin, Zimin Chen

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Май 10, 2023

Abstract The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2), has devastating impacts on the public health and economy. Rapid viral antigenic evolution led to continual generation new variants. Of special note is recently expanding Omicron subvariants that are capable immune evasion from most existing neutralizing antibodies (nAbs). This posed challenges for prevention treatment COVID-19. Therefore, exploring broad-spectrum antiviral agents combat emerging variants imperative. In sharp contrast massive accumulation mutations within SARS-CoV-2 receptor-binding domain (RBD), S2 fusion subunit remained highly conserved among Hence, S2-based therapeutics may provide effective cross-protection against Here, we summarize developed inhibitors (e.g., nAbs, peptides, proteins, small-molecule compounds) candidate vaccines targeting elements in subunit. main focus includes all targetable elements, namely, peptide, stem helix, heptad repeats 1 (HR1-HR2) bundle. Moreover, a detailed summary characteristics action-mechanisms each class cross-reactive inhibitors, which should guide promote future design coronaviruses.

Язык: Английский

Процитировано

47
Key mechanistic features of the trade-off between antibody escape and host cell binding in the SARS-CoV-2 Omicron variant spike proteins DOI Creative Commons
Weiwei Li, Zepeng Xu, Tianhui Niu

и другие.

The EMBO Journal, Год журнала: 2024, Номер 43(8), С. 1484 - 1498

Опубликована: Март 11, 2024

Abstract Since SARS-CoV-2 Omicron variant emerged, it is constantly evolving into multiple sub-variants, including BF.7, BQ.1, BQ.1.1, XBB, XBB.1.5 and the recently emerged BA.2.86 JN.1. Receptor binding immune evasion are recognized as two major drivers for evolution of receptor domain (RBD) spike (S) protein. However, underlying mechanism interplay between factors remains incompletely understood. Herein, we determined structures human ACE2 complexed with XBB RBDs. Based on ACE2/RBD these sub-variants a comparison known complex structures, found that R346T substitution in RBD enhanced upon an interaction residue R493, but not Q493, via involving long-range conformation changes. Furthermore, R493Q F486V exert balanced impact, through which capability was somewhat compromised to achieve optimal binding. We propose “two-steps-forward one-step-backward” model describe such compromise affinity during sub-variants.

Язык: Английский

Процитировано

21
Spike structures, receptor binding, and immune escape of recently circulating SARS-CoV-2 Omicron BA.2.86, JN.1, EG.5, EG.5.1, and HV.1 sub-variants DOI
Linjie Li, Kaiyuan Shi,

Yuhang Gu

и другие.

Structure, Год журнала: 2024, Номер 32(8), С. 1055 - 1067.e6

Опубликована: Июль 15, 2024

Язык: Английский

Процитировано

18
Enabling the immune escaped etesevimab fully-armed against SARS-CoV-2 Omicron subvariants including KP.2 DOI Creative Commons
Chao Su,

Juanhua He,

Yufeng Xie

и другие.

hLife, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

2
Two pan-SARS-CoV-2 nanobodies and their multivalent derivatives effectively prevent Omicron infections in mice DOI Creative Commons
Honghui Liu, Lili Wu, Bo Liu

и другие.

Cell Reports Medicine, Год журнала: 2023, Номер 4(2), С. 100918 - 100918

Опубликована: Янв. 12, 2023

With the widespread vaccinations against coronavirus disease 2019 (COVID-19), we are witnessing gradually waning neutralizing antibodies and increasing cases of breakthrough infections, necessitating development drugs aside from vaccines, particularly ones that can be administered outside hospitals. Here, present two cross-reactive nanobodies (R14 S43) their multivalent derivatives, including decameric (fused to immunoglobulin M [IgM] Fc) maintain potent activity severe acute respiratory syndrome 2 (SARS-CoV-2) after aerosolization display not only pan-SARS-CoV-2 but also varied pan-sarbecovirus activities. Through administration mice, monovalent R14 significantly reduce lung viral RNAs at low dose pre- post-exposure protection. Furthermore, structural studies reveal mechanisms S43 multiple inhibition effects derivatives exert. Our work demonstrates promising convenient drug candidates via SARS-CoV-2 infection, which contribute containing COVID-19 pandemic.

Язык: Английский

Процитировано

35
Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments DOI Creative Commons
Akshita Gupta, Angelina Konnova,

Mathias Smet

и другие.

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(6)

Опубликована: Фев. 2, 2023

BackgroundThe role of host immunity in emergence evasive SARS-CoV-2 Spike mutations under therapeutic monoclonal antibody (mAb) pressure remains to be explored.MethodsIn a prospective, observational, monocentric ORCHESTRA cohort study, conducted between March 2021 and November 2022, mild-to-moderately ill COVID-19 patients (n = 204) receiving bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab were longitudinally studied over 28 days for viral loads, de novo mutations, mAb kinetics, seroneutralization against infecting variants concern, T cell immunity. Additionally, machine learning-based circulating immune-related biomarker (CIB) profile predictive was constructed confirmed an independent data set 19) that included tixagevimab/cilgavimab.ResultsPatients treated with various mAbs developed remarkable speed high specificity the targeted mAb-binding sites. Immunocompromised therapy not only continued display significantly higher but also showed likelihood developing mutations. Development escape mutants strongly correlated neutralizing capacity immunity, suggesting immune as important driver Lastly, we antiinflammatory healing-promoting milieu facilitates where 4 CIBs identified at risk accuracy.ConclusionsOur demonstrate host-driven nonimmune responses are essential development mutant SARS-CoV-2. These support point-of-care decision making reducing treatment failure improving mitigation strategies possible dissemination mutants.FundingThe project/European Union's Horizon 2020 research innovation program.

Язык: Английский

Процитировано

32
Widespread exposure to SARS-CoV-2 in wildlife communities DOI Creative Commons
Amanda R. Goldberg, Kate E. Langwig, Katherine L. Brown

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 29, 2024

Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events animals. While has a potential broad wildlife host range, most documented been captive animals and single species, the white-tailed deer. The full extent of exposure among communities factors that influence risk remain unknown. We sampled 23 species for examined effects urbanization human use on seropositivity. Here, we document positive detections RNA six including deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, red bat between May 2022-September 2023 across Washington, D.C., USA. In addition, found sites with high activity had three times higher seroprevalence than low human-use areas. obtained genomic sequences from nine individuals which were assigned seven Pango lineages Omicron variant. close match variants circulating at time suggests least recent human-to-animal events. Our data support widespread areas may serve as points contact cross-species transmission.

Язык: Английский

Процитировано

15
Neutralization of EG.5, EG.5.1, BA.2.86, and JN.1 by antisera from dimeric receptor-binding domain subunit vaccines and 41 human monoclonal antibodies DOI

Qingwen He,

Yaling An,

Xuemei Zhou

и другие.

Med, Год журнала: 2024, Номер 5(5), С. 401 - 413.e4

Опубликована: Апрель 3, 2024

Язык: Английский

Процитировано

13