Rapid restoration of potent neutralization activity against the latest Omicron variant JN.1 via AI rational design and antibody engineering

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(6)

Опубликована: Фев. 5, 2025

The rapid evolution of the viral genome has led to continual generation new variants SARS-CoV-2. Developing antibody drugs with broad-spectrum and high efficiency is a long-term task. It promising but challenging develop therapeutic neutralizing antibodies (nAbs) through in vitro based on antigen–antibody binding interactions. From an early B cell repertoire, we isolated 8G3 that retains its nonregressive activity against Omicron BA.1 various other strains vitro. protected ACE2 transgenic mice from WA1/2020 virus infection without adverse clinical manifestations completely cleared load lungs. Similar most IGHV3–53 antibodies, sites largely overlap, enabling competition for RBD. By comprehensively considering free energy changes complexes, biological environment their interactions, evolutionary direction were able select 50 mutants. Among them, 11 validated by experiments showing better activities. Further, combination four mutations identified increased neutralization potency JN.1, latest mutant, approximately 1,500-fold, one improvement multiple certain extent. Together, established procedure selection potent SARS-CoV-2 activity. Our results provide reference engineering future even pandemic viruses.

Язык: Английский

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Tendomodulin in pan-cancer analysis: exploring its impact on immune modulation and uncovering functional insights in colorectal cancer

BMC Cancer, Год журнала: 2025, Номер 25(1)

Опубликована: Фев. 11, 2025

Tendomodulin (TNMD) is pivotal in various malignancies, including colorectal cancer (CRC). However, its comprehensive impact across cancers, particularly immunomodulatory function CRC, remains underexplored. This study explored the role of TNMD CRC by focusing on functions through molecular and clinical analyses. Multiple bioinformatics databases analytical tools were utilized for pan-cancer analysis. To validate we performed experiments, immunofluorescence (IF), immunohistochemistry (IHC), real-time quantitative reverse transcription PCR (qPCR), western blotting, cell migration assays. expression gene mutation vary cancers offer high diagnostic value. Survival analysis found that associated with prognosis multiple cancers. Notably, patients microsatellite instability (MSI-H) correlated positively immune cells, natural killer (NK) whereas it was inversely regulatory T cells (Tregs). Crucially, stability (MSS) better immunotherapy outcomes, indicating potential as a biomarker patient stratification tailored treatment approaches. Furthermore, single-cell sequencing data revealed stronger interactions between TNMD-positive tumor fibroblasts or macrophages microenvironment. Finally, overexpressed tissues lines, thereby promoting invasion metastasis. Our findings reveal critical influencing tumor–immune interactions. Beyond prognostic biomarker, promotes metastasis invasion, thus emerging promising therapeutic target. These highlight TNMD's significance potentially other malignancies.

Язык: Английский

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Longitudinal humoral immunity against SARS-CoV-2 Spike following infection in individuals from Cameroon

Virology, Год журнала: 2025, Номер 605, С. 110467 - 110467

Опубликована: Фев. 25, 2025

Язык: Английский

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Deep mutational learning for the selection of therapeutic antibodies resistant to the evolution of Omicron variants of SARS-CoV-2

Nature Biomedical Engineering, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

Most antibodies for treating COVID-19 rely on binding the receptor-binding domain (RBD) of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). However, Omicron and its sub-lineages, as well other heavily mutated variants, have rendered many neutralizing ineffective. Here we show that with enhanced resistance to evolution can be identified via deep mutational learning. We constructed a library full-length RBDs BA.1 high distance screened it angiotensin-converting-enzyme-2 receptor antibodies. After deep-sequencing library, used data train ensemble deep-learning models prediction escape panel eight therapeutic antibody candidates targeting diverse range RBD epitopes. By using in silico assess breadth millions sequences, found combinations two complementary viral evolution. Deep learning may enable development remain effective against future variants.

Язык: Английский

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Molecular mechanisms of RaTG13 and SARS‐CoV‐2 RBD bound to Rhinolophus affinis bat ACE2

Protein Science, Год журнала: 2025, Номер 34(5)

Опубликована: Апрель 22, 2025

The discovery of the RaTG13 coronavirus in Rhinolophus affinis bats 2013, sharing 96.3% genome homology with severe acute respiratory syndrome 2 (SARS-CoV-2), suggested as origin SARS-CoV-2. Although both human angiotensin-converting enzyme (hACE2) and bat ACE2 (bACE2-Ra, seven polymorphic variants named 01-07) are known to serve entry receptors for these coronaviruses, binding mechanism receptor domain (RBD) bound bACE2-Ra remains poorly understood. Here, we found that RBD bACE2-Ra-07 a weaker affinity (2.42 μM) compared SARS-CoV-2 (372 nM). Additional glycosylation at residue N370 had little influence on by RBD. Crystal structures N370Q were solved. Interface analysis surface plasmon resonance (SPR) assay indicated substitutions 493, 498, 501, 505 may play more important role cross-species recognition Besides, mutation enhanced between pangolin isolated from Guangxi (PCoV-GX) over 10-fold. Furthermore, recently prevalent variant RBDs extensively retained interaction receptor. Our findings give new lights evolution prompt urgency monitor circulation coronaviruses better prevent future spillover.

Язык: Английский

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