COVID-19 therapeutics

Clinical Microbiology Reviews, Journal Year: 2024, Volume and Issue: 37(2)

Published: May 21, 2024

SUMMARYSince the emergence of COVID-19 in 2020, an unprecedented range therapeutic options has been studied and deployed. Healthcare providers have multiple treatment approaches to choose from, but efficacy those often remains controversial or compromised by viral evolution. Uncertainties still persist regarding best therapies for high-risk patients, drug pipeline is suffering fatigue shortage funding. In this article, we review antiviral activity, mechanism action, pharmacokinetics, safety therapies. Additionally, summarize evidence from randomized controlled trials on various antivirals discuss unmet needs which should be addressed.

Language: Английский

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AlphaFold2 Modeling and Molecular Dynamics Simulations of the Conformational Ensembles for the SARS-CoV-2 Spike Omicron JN.1, KP.2 and KP.3 Variants: Mutational Profiling of Binding Energetics Reveals Epistatic Drivers of the ACE2 Affinity and Escape Hotspots of Antibody Resistance

Viruses, Journal Year: 2024, Volume and Issue: 16(9), P. 1458 - 1458

Published: Sept. 13, 2024

The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth fitness due to convergent evolution functional hotspots. These hotspots operate in tandem optimize both receptor binding for effective infection immune evasion efficiency, thereby maintaining overall fitness. lack molecular details on structure, dynamics energetics the latest FLiRT FLuQE with ACE2 antibodies provides a considerable challenge that is explored this study. We combined AlphaFold2-based atomistic predictions structures conformational ensembles spike complexes host dominant JN.1, KP.1, KP.2 KP.3 examine mechanisms underlying role balancing antibody evasion. Using ensemble-based mutational scanning protein residues computations affinities, we identified energy characterized basis epistatic couplings between results suggested existence interactions sites at L455, F456, Q493 positions protect restore ACE2-binding affinity while conferring beneficial escape. To escape mechanisms, performed structure-based profiling several classes displayed impaired neutralization against BA.2.86, KP.3. confirmed experimental data harboring L455S F456L mutations can significantly impair neutralizing activity class 1 monoclonal antibodies, effects mediated by facilitate subsequent convergence Q493E changes rescue binding. Structural energetic analysis provided rationale showing BD55-5840 BD55-5514 bind different epitopes retain efficacy all examined support notion may favor emergence lineages combinations involving mediators control balance high

Language: Английский

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Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 9, 2024

SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated immune resistance of but factors are speculated contribute global dominance, which remain elusive until today. Here, we find that a higher infectivity than in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, demonstrate gained over associates increased entry efficiency conferred by and better cleavage hNECs. Structurally, S455 altered mode binding protein ACE2 at

Language: Английский

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The rising SARS‐CoV‐2 JN.1 variant: evolution, infectivity, immune escape, and response strategies

MedComm, Journal Year: 2024, Volume and Issue: 5(8)

Published: July 29, 2024

The JN.1 variant of COVID-19 has emerged as the dominant strain worldwide since end 2023. As a subclade BA.2.86 variant, harbors unique combination mutations inherited from lineage, notably featuring novel L455S mutation within its receptor-binding motif. This been linked to increased transmissibility and enhanced immune evasion capabilities. During rise JN.1, evidence resistance various monoclonal antibodies reduced cross-neutralization effects XBB.1.5 vaccine have observed. Although public health threat posed by appears relatively low, concerns persist regarding evolutionary trajectory under pressure. review provides comprehensive overview evolving highlighting need for continuous monitoring investigation new variants that could lead widespread infection. It assesses efficacy current vaccines therapeutics against emerging variants, particularly focusing on immunocompromised populations. Additionally, this summarizes potential advancements clinical treatments COVID-19, offering insights optimize prevention treatment strategies. thoroughly evaluates variant's impact implications future therapeutic development, contributing ongoing efforts mitigate risk virus transmission disease severity.

Language: Английский

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Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(8), P. 101668 - 101668

Published: Aug. 1, 2024

We describe the molecular-level composition of polyclonal immunoglobulin G (IgG) anti-spike antibodies from ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, vaccination, or their combination ("hybrid immunity") at monoclonal resolution. Infection primarily triggers S2/N-terminal domain (NTD)-reactive antibodies, whereas vaccination mainly induces anti-receptor-binding (RBD) antibodies. This imprint persists after secondary exposures wherein >60% ensuing hybrid immunity derives original IgG pool. Monoclonal constituents pool can increase breadth, affinity, and prevalence upon exposures, as exemplified by plasma antibody SC27. Following a breakthrough vaccine-induced SC27 gained neutralization breadth potency against SARS-CoV-2 variants zoonotic viruses (half-maximal inhibitory concentration [IC

Language: Английский

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