The Virtual Lab: AI Agents Design New SARS-CoV-2 Nanobodies with Experimental Validation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 12, 2024

Abstract Science frequently benefits from teams of interdisciplinary researchers. However, most scientists don’t have access to experts multiple fields. Fortunately, large language models (LLMs) recently shown an impressive ability aid researchers across diverse domains by answering scientific questions. Here, we expand the capabilities LLMs for science introducing Virtual Lab, AI-human research collaboration perform sophisticated, research. The Lab consists LLM principal investigator agent guiding a team agents with different backgrounds (e.g., chemist agent, computer scientist critic agent), human researcher providing high-level feedback. We design conduct through series meetings, where all discuss agenda, and individual accomplishes specific task. demonstrate power applying it nanobody binders recent variants SARS-CoV-2, which is challenging, open-ended problem that requires reasoning fields biology science. creates novel computational pipeline incorporates ESM, AlphaFold-Multimer, Rosetta designs 92 new nanobodies. Experimental validation those reveals range functional nanobodies promising binding profiles SARS-CoV-2 variants. In particular, two exhibit improved JN.1 or KP.3 while maintaining strong ancestral viral spike protein, suggesting exciting candidates further investigation. This demonstrates rapidly make impactful, real-world discovery.

Язык: Английский

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Early, very high-titre convalescent plasma therapy in clinically vulnerable individuals with mild COVID-19: an international, randomised, open-label trial

EBioMedicine, Год журнала: 2025, Номер 113, С. 105613 - 105613

Опубликована: Фев. 27, 2025

Язык: Английский

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Neutralizing Activity and Viral Escape of Pemivibart by SARS-CoV-2 JN.1 sublineages

Опубликована: Ноя. 10, 2024

Abstract Pemivibart (Pemgarda™/VYD222) was granted Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA) on March 22, 2024, for COVID-19 pre-exposure prophylaxis in immunocompromised individuals. However, its efficacy resistance against JN.1 sublineages have yet to be fully characterized. Here, we first assessed neutralizing activity of a panel VSV-based pseudoviruses representing contemporary sublineages, including XEC, fastest-growing SARS-CoV-2 strain globally, both Vero-E6 Vero-E6-TMPRSS2-T2A-hACE2 (Vero-E6-TA) cells. We then engineered replication-competent vesicular stomatitis virus with spike (rVSVΔG-JN.1) select escape variants performed structural analyses comprehensively map Pemivibart’s mutations. Our results demonstrated that exhibited comparable neutralization patterns cell lines retains broad effectiveness tested. potency remarkably reduced KP.3.1.1 IC 50 values approximately 4.2 µg/mL, about 22-fold higher than JN.1, as well JN.1-derived Pemivibart-escape mutants harbouring low-frequency mutations across strains through mutiple antibody evasion mechanisms Vero-E6-TA Collectively, our findings underscored importance monitoring clinical continue evolve. The profile could provide valuable insights forecasting optimizing emerging variants.

Язык: Английский

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SA55 broadly neutralizes SARS-CoV-2 and robustly prevents viral escape by JN.1 sublineages

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

SARS-CoV-2 monoclonal antibodies remain the only option for prevention or treatment of COVID-19 those with immunodeficiencies drug interactions antiviral agents. Here, we assess neutralizing activity authorized antibody pemivibart and candidate SA55 against major historical currently dominant viral variants, including JN.1 subvariants KP.3.1.1 XEC. Our findings show that demonstrates broad potency while exhibits reduced variants. Then employ replication-competent vesicular stomatitis virus spike (rVSVΔG-JN.1) to select escape variants SA55. Following this, conduct a systematic comparison profiles these two antibodies, revealing is remarkably resilient mutations under selection, which consistent our SPR data indicating possesses substantially stronger binding affinity. Moreover, an immunobridging analysis suggests may have superior clinical efficacy in preventing infection current variant landscape. Together, this work highlights promise as potential therapeutic COVID-19, especially immunocompromised populations.

Язык: Английский

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Development of antiviral drugs for COVID-19 in 2025: unmet needs and future challenges

Expert Review of Anti-infective Therapy, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

The success in the COVID-19 pandemic containment largely originated from vaccine- and infection-elicited immunity, with SARS-CoV-2 infection only marginally mitigated by availability of antiviral drugs. current lack effective prophylactic therapeutic agents immunocompromised patients highlights need for a radical change design both drug manufacturing clinical trials. In this review authors summarize their suggestions manufacturers, reviewing classes small molecule antivirals passive immunotherapies highlighting limitations unexploited potential. Molecular serological testing can improve appropriateness. Efficacy be improved combining different while preserving economical sustainability. Respiratory delivery should better investigated

Язык: Английский

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SARS-CoV-2 Fusion Peptide-Directed Antibodies Elicited by Natural Infection Mediate Broad Sarbecovirus Neutralization

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

SUMMARY Studies have demonstrated that repeated mRNA vaccination enhances the breadth of neutralization against diverse SARS-CoV-2 variants. However, development antibodies capable neutralizing across Coronavirinae subfamily is poorly understood. In this study, we analyze serum samples to determine their and potency identify antigenic targets. Using a cohort older individuals healthcare workers, track correlates broad responses, including fusion peptide (FP) antibody elicitation. We find although broadly responses are often result RBD-specific antibodies, rare subset donors produce FP-specific responses. Interestingly, not observed in COVID-naive irrespective regimen, but rather, they occur following natural infection or vaccine breakthrough. This study highlights epitope targets underpinning coronaviruses suggests existing vaccines insufficient promote elicitation FP-directed coronavirus antibodies.

Язык: Английский

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Potent bivalent nanobody constructs that protect against the SARS-CoV-2 XBB variant

npj Viruses, Год журнала: 2025, Номер 3(1)

Опубликована: Март 13, 2025

Язык: Английский

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Fresh frozen plasma for neutralizing SARS-CoV-2: “An exploratory cross-sectional study and review of the state of the art”

Enfermedades Infecciosas y Microbiología Clínica, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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Structural Immunology of SARS‐CoV‐2

Immunological Reviews, Год журнала: 2024, Номер unknown

Опубликована: Дек. 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.

Язык: Английский

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Ultrapotent IgA dimeric antibodies neutralize emerging Omicron variants

Journal of Virology, Год журнала: 2024, Номер 99(1)

Опубликована: Дек. 4, 2024

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