Analysis of SARS-CoV-2 mutations associated with resistance to therapeutic monoclonal antibodies that emerge after treatment

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 71, P. 100991 - 100991

Published: July 31, 2023

Language: Английский

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The Mutational Landscape of SARS-CoV-2

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 9072 - 9072

Published: May 22, 2023

Mutation research is crucial for detecting and treating SARS-CoV-2 developing vaccines. Using over 5,300,000 sequences from genomes custom Python programs, we analyzed the mutational landscape of SARS-CoV-2. Although almost every nucleotide in genome has mutated at some time, substantial differences frequency regularity mutations warrant further examination. C>U are most common. They found largest number variants, pangolin lineages, countries, which indicates that they a driving force behind evolution Not all genes have same way. Fewer non-synonymous single variations encode proteins with critical role virus replication than ancillary roles. Some genes, such as spike (S) nucleocapsid (N), show more others. prevalence target regions COVID-19 diagnostic RT-qPCR tests generally low, cases, primers bind to N gene, it significant. Therefore, ongoing monitoring crucial. The Portal provides access database mutations.

Language: Английский

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Markov State Models and Perturbation-Based Approaches Reveal Distinct Dynamic Signatures and Hidden Allosteric Pockets in the Emerging SARS-Cov-2 Spike Omicron Variant Complexes with the Host Receptor: The Interplay of Dynamics and Convergent Evolution Modulates Allostery and Functional Mechanisms

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(16), P. 5272 - 5296

Published: Aug. 7, 2023

The new generation of SARS-CoV-2 Omicron variants displayed a significant growth advantage and increased viral fitness by acquiring convergent mutations, suggesting that the immune pressure can promote evolution leading to sudden acceleration evolution. In current study, we combined structural modeling, microsecond molecular dynamics simulations, Markov state models characterize conformational landscapes identify specific dynamic signatures spike complexes with host receptor ACE2 for recently emerged highly transmissible XBB.1, XBB.1.5, BQ.1, BQ.1.1 variants. Microsecond simulations Markovian modeling provided detailed characterization functional states revealed thermodynamic stabilization XBB.1.5 subvariant, which be contrasted more BQ.1 subvariants. Despite considerable similarities, mutations induce unique distributions states. results suggested variant-specific changes mobility in interfacial loops receptor-binding domain protein fine-tuned through crosstalk between could provide an evolutionary path modulation escape. By combining atomistic analysis perturbation-based approaches, determined important complementary roles mutation sites as effectors receivers allosteric signaling involved plasticity regulation communications. This study also hidden pockets control distribution flexible adaptable regions.

Language: Английский

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SARS-CoV-2 journey: from alpha variant to omicron and its sub-variants

Infection, Journal Year: 2024, Volume and Issue: 52(3), P. 767 - 786

Published: March 30, 2024

The COVID-19 pandemic has affected hundreds of millions individuals and caused more than six million deaths. prolonged duration the continual inter-individual transmissibility have contributed to emergence a wide variety SARS-CoV-2 variants. Genomic surveillance phylogenetic studies shown that substantial mutations in crucial supersites spike glycoprotein modulate binding affinity evolved SARS-COV-2 lineages ACE2 receptors modify protein with neutralizing antibodies. immunological been associated differential transmissibility, infectivity, therapeutic efficacy vaccines therapies among new This review highlights diverse genetic assimilated various implications acquired related viral transmission, severity are discussed. also addresses effectiveness human antibodies induced by infection or immunization against ascended

Language: Английский

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Using big sequencing data to identify chronic SARS-Coronavirus-2 infections

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

Published: Jan. 20, 2024

Language: Английский

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What makes SARS‐CoV‐2 unique? Focusing on the spike protein

Cell Biology International, Journal Year: 2024, Volume and Issue: 48(4), P. 404 - 430

Published: Jan. 23, 2024

Abstract Severe acute respiratory syndrome‐related coronavirus 2 (SARS‐CoV‐2) seriously threatens public health and safety. Genetic variants determine the expression of SARS‐CoV‐2 structural proteins, which are associated with enhanced transmissibility, virulence, immune escape. Vaccination is encouraged as a intervention, different types vaccines used worldwide. However, new continue to emerge, especially Omicron complex, neutralizing antibody responses diminished significantly. In this review, we outlined uniqueness from three perspectives. First, described detailed structure spike (S) protein, highly susceptible mutations contributes distinct infection cycle virus. Second, systematically summarized immunoglobulin G epitopes highlighted central role nonconserved regions S protein in adaptive Third, provided an overview targeting discussed impact on vaccine effectiveness. The characterization identification genomic organization will help elucidate its mechanisms viral mutation provide basis for selection optimal treatments. leaps advancements regarding improved diagnosis, targeted therapeutic remedies sound evidence showing that scientific understanding, research, technology evolved at pace pandemic.

Language: Английский

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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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spa typing of methicillin-resistant Staphylococcus aureus isolated from domestic animals and veterinary staff in the UK and Ireland

Journal of Antimicrobial Chemotherapy, Journal Year: 2006, Volume and Issue: 58(6), P. 1118 - 1123

Published: Oct. 10, 2006

Region X of the protein A gene (spa) was sequenced from methicillin-resistant Staphylococcus aureus (MRSA) isolates originating animals, humans and environment at veterinary hospitals in UK Ireland. MRSA transmission between animals staff assessed on basis spa typing, PFGE epidemiological data.MRSA dogs (n = 27), horses 9), cats 6), 22) environmental surfaces 3) were analysed by typing. Known contacts human animal carriers ascertained hospitals.All feline, most canine (96%) (82%) showed profiles that either indistinguishable (subtype A1) or closely related (subtypes A2-A10) to epidemic clone EMRSA-15 (CC22), whereas equine (88%) CC8 (types C, D, E G). polymorphism enabled discrimination among strains assigned same type. Fifteen types clustering into two distinct groups detected, with t032 being prevalent (48%). The isolated seven members as those infected attended staff.Irrespective geographical origin, small generally clustered clonal complexes, CC22, respectively. combined use typing allowed better than each method used individually, provided useful information individuals.

Language: Английский

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Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Viruses, Journal Year: 2023, Volume and Issue: 15(5), P. 1143 - 1143

Published: May 10, 2023

Evolutionary and functional studies suggested that the emergence of Omicron variants can be determined by multiple fitness trade-offs including immune escape, binding affinity for ACE2, conformational plasticity, protein stability allosteric modulation. In this study, we systematically characterize dynamics, structural affinities SARS-CoV-2 Spike complexes with host receptor ACE2 BA.2, BA.2.75, XBB.1 XBB.1.5 variants. We combined multiscale molecular simulations dynamic analysis interactions together ensemble-based mutational scanning residues network modeling epistatic interactions. This multifaceted computational study characterized mechanisms identified energetic hotspots mediate predicted increased enhanced BA.2.75 complexes. The results a mechanism driven spatially localized group centers, while allowing functionally beneficial neutral mutations in other interface positions. A network-based community model contributions is proposed revealing key role R498 Y501 mediating community-based couplings sites compensatory dynamics changes. also showed convergent evolutionary hotspot F486 modulate not only local but rewire global communities region F486P mutation to restore both variant which may explain growth advantages over variant. are consistent broad range rationalizing roles form coordinated enabling balance tradeoffs shaping up complex landscape virus transmissibility.

Language: Английский

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Outpatient randomized controlled trials to reduce COVID‐19 hospitalization: Systematic review and meta‐analysis

Journal of Medical Virology, Journal Year: 2023, Volume and Issue: 95(12)

Published: Dec. 1, 2023

Abstract This COVID‐19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period, geography, variants, and vaccine status. Outpatient RCTs with endpoint were identified in Pubmed searches through May 2023, excluding <30 participants (PROSPERO‐CRD42022369181). Risk of bias was extracted from COVID‐19‐NMA, odds ratio utilized for pooled comparison. Searches 281 studies 61 published 33 diverse interventions analyzed. largely unvaccinated cohorts at least one risk factor. Grouping by class, monoclonal antibodies (mAbs) (OR = 0.31 [95% CI 0.24−0.40]) had highest hospital reduction efficacy, followed convalescent plasma (CCP) 0.69 0.53−0.90]), small molecule antivirals 0.78 0.48−1.33]), repurposed drugs 0.82 CI: 0.72−0.93]). Earlier disease onset performed better than later. meta‐analysis allows approximate head‐to‐head comparisons interventions. Omicron sublineages (XBB BQ.1.1) are resistant to mAbs Despite trial heterogeneity, this comparison intervention class indicated oral the preferred where available, but intravenous remdesivir also effective necessary constrained medical resource settings or acute chronic immunocompromised.

Language: Английский

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