SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs

Cell chemical biology, Год журнала: 2024, Номер 31(4), С. 632 - 657

Опубликована: Апрель 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Язык: Английский

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Host cell entry and neutralisation sensitivity of the SARS-CoV-2 XBB.1.16 lineage

Cellular and Molecular Immunology, Год журнала: 2023, Номер 20(8), С. 969 - 971

Опубликована: Май 8, 2023

Despite previous circulation of the highly transmissible and antibody evasive BA.2.75, BQ.1, XBB.1 XBB.1.5lineages, share infections caused by SARS-CoV-2 lineage XBB.1.16has gradually increased in India early 2023, resulting XBB.1.16being dominating today.Since a similar trend may also take place other countries information on biological properties XBB.1.16lineage is scarce, we conducted rapid assessment with respect to its ability enter cells evade neutralisation antibodies.The newly emerged (also dubbed as Arcturus), which harbours unique combination spike (S) protein mutations (Fig. 1a), was first described January 2023 rapidly became (https://covspectrum.org/ [1]) 1b).Here performed regarding antibodies using S proteincarrying pseudovirus particles (pp), constitute suitable model study host cell entry [2].For comparison, bearing ancestral B.1 (B.1 pp ) or proteins Omicron sublineages BA.5 (BA.5 ), CH.1.1 (CH.1.1 (XBB.1 XBB.1.5(XBB.1.5pp were used.In line expectations, entered Vero (African green monkey, kidney), 293 T (human, kidney) Huh-7 liver) higher efficiency compared (1.6-3.9xhigher, respectively), while into Caco-2 colon) Calu-3 lung) less efficient (1.6-1.9xreduced, [3] 1c).CH.1.1 displayed comparable slightly for Vero, (1.1x-1.9xhigher, even (2.3-3.8xreduced, 1c).In accordance literature, XBB.1.5pp generally (1.2-1.5xhigher, [4] same observation made XBB.1.16pp (1.3-1.6xhigher, 1c).

Язык: Английский

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Omicron BQ.1.1 and XBB.1 unprecedentedly escape broadly neutralizing antibodies elicited by prototype vaccination

Cell Reports, Год журнала: 2023, Номер 42(6), С. 112532 - 112532

Опубликована: Май 22, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants have seriously attacked the antibody barrier established by natural infection and/or vaccination, especially recently emerged BQ.1.1 and XBB.1. However, crucial mechanisms underlying virus escape broad neutralization remain elusive. Here, we present a panoramic analysis of broadly neutralizing activity binding epitopes 75 monoclonal antibodies isolated from prototype inactivated vaccinees. Nearly all (nAbs) partly or totally lose their against We report nAb, VacBB-551, that effectively neutralizes tested including BA.2.75, BQ.1.1, determine cryoelectron microscopy (cryo-EM) structure VacBB-551 complexed with BA.2 spike perform detailed functional verification to reveal molecular basis N460K F486V/S mutations mediating partial XBB.1 VacBB-551. Overall, raised alarm over SARS-CoV-2 evolution unprecedented evasion nAbs elicited vaccination.

Язык: Английский

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Spatiotemporal dynamics and epidemiological impact of SARS-CoV-2 XBB lineage dissemination in Brazil in 2023

Microbiology Spectrum, Год журнала: 2024, Номер 12(3)

Опубликована: Фев. 5, 2024

ABSTRACT The SARS-CoV-2 XBB is a group of highly immune-evasive lineages the Omicron variant concern that emerged by recombining BA.2-descendent and spread worldwide during 2023. In this study, we combine genomic data ( n = 11,065 sequences) with epidemiological severe acute respiratory infection (SARI) cases collected in Brazil between October 2022 July 2023 to reconstruct space-time dynamics epidemiologic impact dissemination country. Our analyses revealed introduction local emergence carrying convergent mutations within Spike protein, especially F486P, F456L, L455F, propelled XBB* Brazil. average relative instantaneous reproduction numbers + F486P F456L L455F were estimated be 1.24, 1.33, 1.48 higher than other co-circulating (mainly BQ.1*/BE*), respectively. Despite such growth advantage, these had reduced on Brazil’s scenario concerning previous subvariants. peak number SARI from wave was approximately 90%, 80%, 70% lower observed BA.1*, BA.5*, BQ.1* waves, These findings multiple progressively increasing yet relatively limited throughout stand out for their heightened transmissibility, warranting close monitoring months ahead. IMPORTANCE one most affected countries pandemic, more 700,000 deaths mid-2023. This study reconstructs virus country first half 2023, period characterized descendants XBB.1, recombinant BA.2 evolved late 2022. analysis supports marked continuous indigenous bearing similar key sites process followed increments without repercussions incidence cases. Thus, results suggest influenced an intricate interplay factors extend beyond virus's transmissibility alone. also underlines need surveillance allows its ever-shifting composition.

Язык: Английский

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Characterization of Omicron BA.4.6, XBB, and BQ.1.1 subvariants in hamsters

Communications Biology, Год журнала: 2024, Номер 7(1)

Опубликована: Март 15, 2024

Abstract During the Omicron wave, previous variants such as BA.2, BA.4, and BA.5 were replaced by newer with additional mutations in spike protein. These variants, BA.4.6, BQ.1.1, XBB, have spread different countries degrees of success. Here, we evaluated replicative ability pathogenicity BQ1.1, XBB clinical isolates male Syrian hamsters. Although found no substantial differences weight change among hamsters infected these subvariants, BQ.1.1 lung tissue was higher than that BA.4.6 BA.5. Of note, lethal both female transgenic human ACE2 In competition assays, replicated better nasal turbinate tissues previously BA.2. results suggest subvariants family are still evolving should be closely monitored.

Язык: Английский

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Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals

Antiviral Research, Год журнала: 2024, Номер 225, С. 105869 - 105869

Опубликована: Март 26, 2024

SARS-CoV-2 Omicron subvariants with increased transmissibility and immune evasion are spreading globally alarming persistence. Whether the mutations evolution of spike (S) alter viral hijacking human TMPRSS2 for entry remains to be elucidated. This is particularly important investigate because large number diversity S reported since emergence BA.1. Here we report that a molecular determinant all clinical isolates tested in lung cells, including ancestral (BA.1, BA.2, BA.5), contemporary (BQ.1.1, XBB.1.5, EG.5.1) currently circulating BA.2.86. First, used co-transfection assay demonstrate endoproteolytic cleavage by subvariants. Second, found N-0385, highly potent inhibitor, robust inhibitor virus-like particles harbouring protein Third, show N-0385 exhibits nanomolar broad-spectrum antiviral activity against live Calu-3 cells primary patient-derived bronchial epithelial cells. Interestingly, 10-20 times more than repositioned camostat, BA.5, EG.5.1, We further shows broad synergistic clinically approved direct-acting antivirals (DAAs), i.e., remdesivir nirmatrelvir, subvariants, demonstrating potential therapeutic benefits multi-targeted treatment based on DAAs.

Язык: Английский

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Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein

Clinical Infectious Diseases, Год журнала: 2023, Номер 77(7), С. 950 - 960

Опубликована: Июнь 17, 2023

Patients with antibody deficiency respond poorly to coronavirus disease 2019 (COVID-19) vaccination and are at risk of severe or prolonged infection. They given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma confer passive immunity against Following widespread COVID-19 alongside natural exposure, we hypothesized that preparations will now contain neutralizing acute respiratory syndrome 2 (SARS-CoV-2) spike antibodies, which protection may help treat chronic

Язык: Английский

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XBB.1.5 neutralizing antibodies upon bivalent COVID‐19 vaccination are similar to XBB but lower than BQ.1.1

American Journal of Hematology, Год журнала: 2023, Номер 98(5)

Опубликована: Фев. 22, 2023

The COVID-19 virus has evolved significantly from the ancestral WA1/2020 strain over past 3 years with new sublineages, subvariants, and recombinant strains emerging causing waves of infections.1 During 2022, Omicron B.1.1.529 sublineages have been spreading world-wide a recent rapidly XBB.1.5 variant reported (www.gisaid.org). This prompted analysis vaccine induced neutralizing antibody (NAb) to evaluate protective efficacy newly circulating variants. Our results show lower but detectable activity newer variants including XBB.1.5, suggesting continuing benefit current bivalent (WA1/BA.5) vaccine. Because anti-Spike immunity is known decline overtime, booster vaccinations in previously boosted individuals or after BA.5 breakthrough infection are justified because they increase enhance probability neutralize further evolving Due erosion by variants, timely updating future vaccines remains one most important issues fight against COVID. Although different proteins contribute SARS-CoV-2 pathogenesis, Spike particular interest facilitate cell entry via ACE2 receptor protein, an interaction that directly affects transmissibility impacts on efficacy. first generation used protein. We others vaccine-induced provided reduced neutralization BA.1.529.1 subvariants BA.4 BA.5, which share identical (Supplemental Methods). BA.4/5 differs WA1 at 18 amino acids (AA) located within Receptor Binding Domain (RBD) mutations L452R, F486V, R493Q (Figure 1A). second comprising mRNA both proteins, improved BA.4/5. However, emergence additional raised concerns about breadth strength NAb. Of concern multiple changes RBD key sites receptor. BQ.1 sublineage positions R346T, K444T, N460K. RBDs XBB XBB1.5 L368I, V445P, N460K, F490S differ mutation F486S (XBB) F486P (XBB.1.5), rarely seen AA change emerged late 2022.2, alerted medical community possible impact NAb In this part NCT04743388 study, we evaluated magnitude targeting WA1, recently SARS CoV-2 vaccinated (monovalent bivalent) cohorts cohort Greece. Major inclusion criteria included: (i) age above years; (II) ability sign informed consent form (iii) eligibility for vaccination, according national program vaccination. exclusion included presence of: autoimmune disorder under immunosuppressive therapy; (ii) active malignant disease end-stage renal disease, as described.4 BA.1/BA.2 during spring 2022 Greece were largely replaced summer5 1B). more include BQ.1.1 introduced XBB.1.5.5 median participants (n = 79) was 56.5 (range 22–100), whereas 28 (35.4%) males body mass index 25.6 kg/m2 17.6–35.9). Ten (12.6%) had hypercholesterolemia 21 (26.5%) hypertension. history monovalent vaccination lack thereof 1C). 21) received prior three doses BNT162b2 (Pfizer/BioNTech) (Table S1). Fourteen also infected (likely BA.1/BA.2, 2022; www.gisaid.org) October 3–7 months post-infection. 37) manufacturers did not receive S2). occurred July August when dominant analyzed cross-neutralizing 1 month last 3–5 post-COVID (BA.5) infection. Sera tested their pseudotyped viruses carrying panel XBB, well Information). assay D614G mutation, shared all other All showed robust WA1. Both ~3-5-fold higher titers than 1D, E). contrast, 1F) (>10-fold) levels described patients myeloma Waldenstrom's Macroglobulinemia.6 agreement others, these data greatly augmented level strain-specific limited WA1-induced BA.5. To address cross-neutralization capability compared BQ.1.1, divergent BA.2 recombinant, infectious XBB.1.5. similar readouts being marked significant reductions (~5-fold) (~10-fold), demonstrating escape host immune responses. No difference relative decreases found comparing two cohorts. Importantly, great finding 20–30% very low no NAb, below threshold Prior outcome. suggested need there demonstrated superiority wane time and/or namely There decrease Interestingly, between found, indicating F480S P effect antigenic escape. Thus, despite rapid majority variant, albeit level. note, ~30% detection. real-life overall be evaluated. light observed waning upon vaccinations, relate evolutionary leaps, raises makes development urgent matter. contrast cohort, dramatically BQ1.1 ~50% ~80% recipients. Together, WA-1 corroborate importance As expansion previous reports effectiveness mono- addressing XBB2, 3, 7-10 report, provide insights showing mutants, enhanced evasive properties sublineages. spread likely associated increased rather evasion. response rate BQ concern. continuous evolution diminishing breadth, supports using Evangelos Terpos, Meletios-Athanasios Dimopoulos, George N. Pavlakis, Barbara K. Felber conceived designed study. Ioannis Ntanasis-Stathopoulos, Stamatia Skourti, Panagiotis Malandrakis, Trougakos, Dimopoulos resources, supervised, collected, processed patient samples; Santhi Devasundaram, Margherita Rosati, Jenifer Bear, Robert Burns, Felber, Pavlakis performed experiments analysis; Terpos drafted manuscript. authors reviewed edited manuscript gave final approval submitted version. thank members labs discussions, T. Jones assistance. Bagratuni, A. Papadimou, C-I. Liacos technical work supported funding Intramural Research Program, National Institutes Health, Cancer Institute, Center Felber. content publication does necessarily reflect views policies Department Health Human Services, nor mention trade names, commercial products, organizations imply endorsement U.S. Government. honoraria Astra/Zeneca Pfizer. declared conflicts. support findings study available corresponding reasonable request. Table S1. Bivalent S2. Breakthrough Please note: publisher responsible functionality any supporting information supplied authors. Any queries (other missing content) should directed author article.

Язык: Английский

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The effects of amino acid substitution of spike protein and genomic recombination on the evolution of SARS-CoV-2

Frontiers in Microbiology, Год журнала: 2023, Номер 14

Опубликована: Июль 25, 2023

Over three years’ pandemic of 2019 novel coronavirus disease (COVID-19), multiple variants and subvariants have emerged successively, outcompeted earlier become predominant. The sequential emergence reflects the evolutionary process mutation-selection-adaption severe acute respiratory syndrome 2 (SARS-CoV-2). Amino acid substitution/insertion/deletion in spike protein causes altered viral antigenicity, transmissibility, pathogenicity SARS-CoV-2. Early pandemic, D614G mutation conferred virus with advantages over previous increased it also laid a conservative background for subsequent substantial mutations. role genomic recombination evolution SARS-CoV-2 raised increasing concern occurrence recombinants such as Deltacron, XBB.1.5, XBB.1.9.1, XBB.1.16 late phase pandemic. Co-circulation different co-infection immunocompromised patients accelerate recombinants. Surveillance variations, particularly recombination, is essential to identify ongoing changes genome antigenic epitopes thus leads development new vaccine strategies interventions.

Язык: Английский

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Exploring the structural and molecular interaction landscape of nirmatrelvir and Mpro complex: The study might assist in designing more potent antivirals targeting SARS-CoV-2 and other viruses

Journal of Infection and Public Health, Год журнала: 2023, Номер 16(12), С. 1961 - 1970

Опубликована: Сен. 30, 2023

Several therapeutics have been developed and approved against SARS-CoV-2 occasionally; nirmatrelvir is one of them. The drug target Mpro, therefore, it necessary to comprehend the structural molecular interaction Mpro-nirmatrelvir complex.Integrative bioinformatics, system biology, statistical models were used analyze macromolecular complex.Using two complexes, study illustrated interactive residues, H-bonds, interfaces. It informed six nine H-bond formations for first second complex, respectively. maximum bond length was observed as 3.33 Å. ligand binding pocket's surface area volume noted 303.485 Å2 295.456 Å3 complex 308.397 304.865 complex. proteome dynamics evaluated by analyzing complex's NMA mobility, eigenvalues, deformability, B-factor. Conversely, a model created assess therapeutic status nirmatrelvir.Our reveals landscape will guide researchers in designing more broad-spectrum antiviral molecules mimicking nirmatrelvir, which assist fighting other infectious viruses. also help prepare future epidemics or pandemics.

Язык: Английский

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