Development of the TSR-based computational method to investigate spike and monoclonal antibody interactions

Frontiers in Chemistry, Journal Year: 2025, Volume and Issue: 13

Published: March 19, 2025

Introduction Monoclonal antibody (mAb) drug treatments have proven effective in reducing COVID-19-related hospitalizations or fatalities, particularly among high-risk patients. Numerous experimental studies explored the structures of spike proteins and their complexes with ACE2 mAbs. These 3D provide crucial insights into interactions between mAb, forming a basis for development diagnostic tools therapeutics. However, field computational biology has faced substantial challenges due to lack methods precise protein structural comparisons accurate prediction molecular interactions. In our previous studies, we introduced Triangular Spatial Relationship (TSR)-based algorithm, which represents protein’s structure using vector integers (keys). earlier however, were limited individual proteins. Purpose This study introduces new extensions TSR-based enhancing its ability two molecules. We apply these gain mechanistic understanding - mAb Method expanded basic TSR method three novel ways: (1) keys encompassing all atoms, (2) cross molecules, (3) intra-residual amino acids. representation offers unique advantage by simplifying search similar substructures within datasets. Results The study’s key findings include: (i) effectively quantified interpreted conformational changes steric effects newly keys. (ii) Six clusters CDRH3 CDRL3 identified all-atom (iii) constructed TSR-STRSUM (TSR-STRucture SUbstitution Matrix), matrix that pairwise similarities acid structures, providing valuable applications sequence comparison. (iv) Intra-residual revealed distinct Tyr characterized specific triangle geometries. Conclusion presents an advanced approach not only quantifies interprets backbones, entire acids, but also facilitates induced binding across some instances, direct correlation functions was successfully established.

Language: Английский

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A novel genotyping system based on site polymorphism on spike gene reveals the evolutionary pathway of porcine epidemic diarrhea virus

iMetaOmics., Journal Year: 2025, Volume and Issue: unknown

Published: April 6, 2025

Abstract Porcine epidemic diarrhea virus (PEDV) is a lethal coronavirus in neonatal piglets characterized by rapid evolution both genotype and phenotype. However, the underlying genetic mechanism has not been completely elucidated. In this study, we investigated PEDV field strains circulating China between 2021 2022, which revealed significant divergence. To improve classification of PEDV, developed site‐polymorphism‐based genotyping system utilizing global sequences from public databases. While there are currently multiple genotypic classification‐based systems for our proposed approach could offer more stable considering characteristics evolutionary dynamics. Our analysis indicates that most prevalent lineages originated South Korea China, with G2c: L4 predominating L10 United States. Importantly, discrete phylogenetic potential pathways showing termini S gene prone to recombination, while adaptive selection evident middle region. Overall, findings provide complementary practical methodology novel insights into pathway coronaviruses.

Language: Английский

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Structural Immunology of SARS‐CoV‐2

Immunological Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 27, 2024

The SARS-CoV-2 spike (S) protein has undergone significant evolution, enhancing both receptor binding and immune evasion. In this review, we summarize ongoing efforts to develop antibodies targeting various epitopes of the S protein, focusing on their neutralization potency, breadth, escape mechanisms. Antibodies receptor-binding site (RBS) typically exhibit high neutralizing potency but are frequently evaded by mutations in variants. contrast, conserved regions, such as S2 stem helix fusion peptide, broader reactivity generally lower potency. However, several broadly have demonstrated exceptional efficacy against emerging variants, including latest omicron subvariants, underscoring potential vulnerable sites RBS-A RBS-D/CR3022. We also highlight public classes different protein. targeted present opportunities for germline-targeting vaccine strategies. Overall, developing escape-resistant, potent effective vaccines remains crucial combating future This review emphasizes importance identifying key utilizing antibody affinity maturation inform therapeutic design.

Language: Английский

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Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(10), P. e1012650 - e1012650

Published: Oct. 28, 2024

The recurring spillover of pathogenic coronaviruses and demonstrated capacity sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need better understand immune responses this virus family. For purpose, we characterized functional breadth potency antibodies targeting receptor binding domain (RBD) spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 sarbecoviruses from diverse clades animal origins with potential. One neutralizing antibody, C68.61, showed remarkable neutralization both variants viruses different sarbecovirus clades. which targets a conserved RBD class 5 epitope, did not select for escape or culture nor have predicted among circulating strains, suggesting epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive target more sequence 4 epitopes within show activity subset one antibody every single tested. A these Fc-mediated effector functions as potent impact infection outcome models. Thus, our study regions across may serve therapeutics pandemic preparedness well blueprints design immunogens capable eliciting cross-neutralizing responses.

Language: Английский

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Discovery of anti-SARS-CoV-2 S2 protein antibody CV804 with broad-spectrum reactivity with various beta coronaviruses and analysis of its pharmacological properties in vitro and in vivo

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(12), P. e0300297 - e0300297

Published: Dec. 2, 2024

The SARS-CoV-2 pandemic alerted the potential for significant harm due to future cross-species transmission of various animal coronaviruses human. There is a need antibody-based drugs treat patients infected with previously unseen coronaviruses. In this study, we generated CV804, an antibody that binds S2 domain spike protein, which highly conserved across coronavirus family and less susceptible mutations. CV804 demonstrated broad cross-reactivities not only disease-associated human beta including SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-HKU1 existing mutant strains but also 20 representative animal-origin exhibits strong antibody-dependent cellular cytotoxicity (ADCC) protein expressed on cells in vitro , while completely lacks virus-neutralization activity. models, suppressed disease progression caused by infection. Structural studies using HDX-MS combined reactivity analysis point mutants recombinant proteins revealed unique conformational epitope within among Overall, obtained data suggest non-neutralizing recognizes structure displayed surface weakens viral virulence supporting host immune cells’ attack through ADCC activity vivo . information study useful designing pan-corona therapeutics universal vaccines preparing pandemics.

Language: Английский

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