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1.
Science ; 385(6710): 757-765, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39146425

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the receptor angiotensin converting enzyme 2 (ACE2) and drives virus-host membrane fusion through refolding of its S2 domain. Whereas the S1 domain contains high sequence variability, the S2 domain is conserved and is a promising pan-betacoronavirus vaccine target. We applied cryo-electron tomography to capture intermediates of S2 refolding and understand inhibition by antibodies to the S2 stem-helix. Subtomogram averaging revealed ACE2 dimers cross-linking spikes before transitioning into S2 intermediates, which were captured at various stages of refolding. Pan-betacoronavirus neutralizing antibodies targeting the S2 stem-helix bound to and inhibited refolding of spike prehairpin intermediates. Combined with molecular dynamics simulations, these structures elucidate the process of SARS-CoV-2 entry and reveal how pan-betacoronavirus S2-targeting antibodies neutralize infectivity by arresting prehairpin intermediates.


Asunto(s)
Enzima Convertidora de Angiotensina 2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Microscopía por Crioelectrón , Simulación de Dinámica Molecular , Dominios Proteicos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Humanos , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/química , Internalización del Virus , Replegamiento Proteico , Tomografía con Microscopio Electrónico , Multimerización de Proteína , Betacoronavirus/inmunología , Betacoronavirus/química , Membrana Celular/metabolismo , COVID-19/virología , COVID-19/inmunología , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo
2.
Nat Commun ; 14(1): 6710, 2023 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-37872202

RESUMEN

The HIV-1 entry inhibitor temsavir prevents the viral receptor CD4 (cluster of differentiation 4) from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do this, temsavir relies on the presence of a residue with small side chain at position 375 in Env and is unable to neutralize viral strains like CRF01_AE carrying His375. Here we investigate the mechanism of temsavir resistance and show that residue 375 is not the sole determinant of resistance. At least six additional residues within the gp120 inner domain layers, including five distant from the drug-binding pocket, contribute to resistance. A detailed structure-function analysis using engineered viruses and soluble trimer variants reveals that the molecular basis of resistance is mediated by crosstalk between His375 and the inner domain layers. Furthermore, our data confirm that temsavir can adjust its binding mode to accommodate changes in Env conformation, a property that likely contributes to its broad antiviral activity.


Asunto(s)
Fármacos Anti-VIH , Inhibidores de Fusión de VIH , Infecciones por VIH , VIH-1 , Humanos , VIH-1/fisiología , Fármacos Anti-VIH/uso terapéutico , Proteína gp120 de Envoltorio del VIH/genética
3.
Front Immunol ; 14: 1178355, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37334379

RESUMEN

SARS-CoV-2, the virus behind the COVID-19 pandemic, has changed over time to the extent that the current virus is substantially different from what originally led to the pandemic in 2019-2020. Viral variants have modified the severity and transmissibility of the disease and continue do so. How much of this change is due to viral fitness versus a response to immune pressure is hard to define. One class of antibodies that continues to afford some level of protection from emerging variants are those that closely overlap the binding site for angiotensin-converting enzyme 2 (ACE2) on the receptor binding domain (RBD). Some members of this class that were identified early in the course of the pandemic arose from the VH 3-53 germline gene (IGHV3-53*01) and had short heavy chain complementarity-determining region 3s (CDR H3s). Here, we describe the molecular basis of the SARS-CoV-2 RBD recognition by the anti-RBD monoclonal antibody CoV11 isolated early in the COVID-19 pandemic and show how its unique mode of binding the RBD determines its neutralization breadth. CoV11 utilizes a heavy chain VH 3-53 and a light chain VK 3-20 germline sequence to bind to the RBD. Two of CoV11's four heavy chain changes from the VH 3-53 germline sequence, ThrFWR H128 to Ile and SerCDR H131 to Arg, and some unique features in its CDR H3 increase its affinity to the RBD, while the four light chain changes from the VK 3-20 germline sequence sit outside of the RBD binding site. Antibodies of this type can retain significant affinity and neutralization potency against variants of concern (VOCs) that have diverged significantly from original virus lineage such as the prevalent omicron variant. We also discuss the mechanism by which VH 3-53 encoded antibodies recognize spike antigen and show how minimal changes to their sequence, their choice of light chain, and their mode of binding influence their affinity and impact their neutralization breadth.


Asunto(s)
Antígenos de Grupos Sanguíneos , COVID-19 , Humanos , Pandemias , SARS-CoV-2 , Familia de Multigenes , Anticuerpos
4.
bioRxiv ; 2023 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-37131729

RESUMEN

The HIV-1 entry inhibitor temsavir prevents CD4 from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do this temsavir relies on the presence of a residue with small side chain at position 375 in Env and is unable to neutralize viral strains like CRF01_AE carrying His375. Here we investigate the mechanism of temsavir-resistance and show that residue 375 is not the sole determinant of resistance. At least six additional residues within the gp120 inner domain layers, including five distant from the drug-binding pocket, contribute to resistance. A detailed structure-function analysis using engineered viruses and soluble trimer variants reveal that the molecular basis of resistance is mediated by crosstalk between His375 and the inner domain layers. Furthermore, our data confirm that temsavir can adjust its binding mode to accommodate changes in Env conformation, a property that likely contributes to its broad-antiviral activity.

5.
Nat Commun ; 14(1): 755, 2023 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-36765047

RESUMEN

Bile salt hydrolase (BSH) in Bacteroides is considered a potential drug target for obesity-related metabolic diseases, but its involvement in colon tumorigenesis has not been explored. BSH-expressing Bacteroides is found at high abundance in the stools of colorectal cancer (CRC) patients  with overweight and in the feces of a high-fat diet (HFD)-induced CRC mouse model. Colonization of B. fragilis 638R, a strain with low BSH activity, overexpressing a recombinant bsh gene from B. fragilis NCTC9343 strain, results in increased unconjugated bile acids in the colon and accelerated progression of CRC under HFD treatment. In the presence of high BSH activity, the resultant elevation of unconjugated deoxycholic acid and lithocholic acid activates the G-protein-coupled bile acid receptor, resulting in increased ß-catenin-regulated chemokine (C-C motif) ligand 28 (CCL28) expression in colon tumors. Activation of the ß-catenin/CCL28 axis leads to elevated intra-tumoral immunosuppressive CD25+FOXP3+ Treg cells. Blockade of the ß-catenin/CCL28 axis releases the immunosuppression to enhance the intra-tumoral anti-tumor response, which decreases CRC progression under HFD treatment. Pharmacological inhibition of BSH reduces HFD-accelerated CRC progression, coincident with suppression of the ß-catenin/CCL28 pathway. These findings provide insights into the pro-carcinogenetic role of Bacteroides in obesity-related CRC progression and characterize BSH as a potential target for CRC prevention and treatment.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Animales , Ratones , Bacteroides/genética , Bacteroides/metabolismo , beta Catenina/metabolismo , Amidohidrolasas/genética , Carcinogénesis , Obesidad/complicaciones , Ácidos y Sales Biliares , Neoplasias Colorrectales/patología
6.
iScience ; 26(1): 105783, 2023 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-36514310

RESUMEN

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

7.
Cell Rep ; 41(6): 111624, 2022 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-36351384

RESUMEN

Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to "open" Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses.


Asunto(s)
Infecciones por VIH , Seropositividad para VIH , VIH-1 , Animales , Humanos , Ratones , Anticuerpos Neutralizantes , Citotoxicidad Celular Dependiente de Anticuerpos , Anticuerpos Anti-VIH
8.
Viruses ; 14(10)2022 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-36298733

RESUMEN

SARS-CoV-2 continues to infect millions of people worldwide. The subvariants arising from the variant-of-concern (VOC) Omicron include BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4, and BA.5. All possess multiple mutations in their Spike glycoprotein, notably in its immunogenic receptor-binding domain (RBD), and present enhanced viral transmission. The highly mutated Spike glycoproteins from these subvariants present different degrees of resistance to recognition and cross-neutralisation by plasma from previously infected and/or vaccinated individuals. We have recently shown that the temperature affects the interaction between the Spike and its receptor, the angiotensin converting enzyme 2 (ACE2). The affinity of RBD for ACE2 is significantly increased at lower temperatures. However, whether this is also observed with the Spike of Omicron and sub-lineages is not known. Here we show that, similar to other variants, Spikes from Omicron sub-lineages bind better the ACE2 receptor at lower temperatures. Whether this translates into enhanced transmission during the fall and winter seasons remains to be determined.


Asunto(s)
Enzima Convertidora de Angiotensina 2 , COVID-19 , Humanos , SARS-CoV-2/genética , Temperatura , Glicoproteína de la Espiga del Coronavirus/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Mutación
9.
Chemosphere ; 308(Pt 1): 136228, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36041522

RESUMEN

Pyrite was applied to Cr(VI) bioremediation as an inorganic electron donor due to the ability to provide electrons, while the role of pyrite in Cr(VI) bioremediation where organics as electron donors remains unknown. Herein a pyrite-based Cr(VI) bioreduction process in the sediment system containing lactate was demonstrated to be effective to detoxify Cr(VI): over 2200 mg L-1 Cr(VI) was continuously removed within 210 h with high reactivity (10.5 mg/(L·h)) all along. High-throughput 16S rDNA gene sequencing indicated that the pyrite could shape a functioning community that electrochemically active bacteria dominated (such as Fusibacter sp. and Rhodobacteraceae) instead of iron-oxidizing bacteria and sulfur-oxidizing bacteria. Mineralogy analysis results indicated that Fe(III), S22- and S0 formed on the pyrite surface after the oxidation of Cr(VI) might serve as the electron acceptor of microflora, then the S2- and Fe(II) with strong Cr(VI) reduction ability were formed by microbial reduction to enhance the removal of Cr(VI). This study provides new insights into thoroughly understanding the role of pyrite in the practical application of Cr(VI) bioreduction.


Asunto(s)
Compuestos Férricos , Hierro , Bacterias/genética , Cromo , ADN Ribosómico , Compuestos Ferrosos , Lactatos , Sustancias Reductoras , Sulfuros , Azufre
10.
Sci Adv ; 8(28): eabn4188, 2022 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-35857504

RESUMEN

Soluble angiotensin-converting enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses using ACE2 as their receptor. Using structure-guided approaches, we developed a series of bivalent ACE2-Fcs harboring functionally and structurally validated mutations that enhance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain recognition by up to ~12-fold and remove angiotensin enzymatic activity. The lead variant M81 potently cross-neutralized SARS-CoV-2 variants of concern (VOCs), including Omicron, at subnanomolar half-maximal inhibitory concentration and was capable of robust Fc-effector functions, including antibody-dependent cellular cytotoxicity, phagocytosis, and complement deposition. When tested in a stringent K18-hACE2 mouse model, Fc-enhanced ACE2-Fc delayed death by 3 to 5 days or effectively resolved lethal SARS-CoV-2 infection in both prophylactic and therapeutic settings via the combined effects of neutralization and Fc-effector functions. These data add to the demonstrated utility of soluble ACE2 as a valuable SARS-CoV-2 antiviral and indicate that Fc-effector functions may constitute an important component of ACE2-Fc therapeutic activity.

11.
iScience ; 25(7): 104528, 2022 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-35677392

RESUMEN

SARS-CoV-2 infection of host cells starts by binding the Spike glycoprotein (S) to the ACE2 receptor. The S-ACE2 interaction is a potential target for therapies against COVID-19 as demonstrated by the development of immunotherapies blocking this interaction. VE607 - a commercially available compound composed of three stereoisomers - was described as an inhibitor of SARS-CoV-1. Here, we show that VE607 broadly inhibits pseudoviral particles bearing the Spike from major VOCs (D614G, Alpha, Beta, Gamma, Delta, Omicron - BA.1, and BA.2) as well as authentic SARS-CoV-2 at low micromolar concentrations. In silico docking, mutational analysis, and smFRET revealed that VE607 binds to the receptor binding domain (RBD)-ACE2 interface and stabilizes RBD in its "up" conformation. Prophylactic treatment with VE607 did not prevent SARS-CoV-2-induced mortality in K18-hACE2 mice, but it did reduce viral replication in the lungs by 37-fold. Thus, VE607 is an interesting lead for drug development for the treatment of SARS-CoV-2 infection.

12.
MAbs ; 14(1): 2047144, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35289719

RESUMEN

There remains an unmet need for globally deployable, low-cost therapeutics for the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Previously, we reported on the isolation and in vitro characterization of a potent single-domain nanobody, NIH-CoVnb-112, specific for the receptor-binding domain (RBD) of SARS-CoV-2. Here, we report on the molecular basis for the observed broad in vitro neutralization capability of NIH-CoVnb-112 against variant SARS-CoV-2 pseudoviruses. The structure of NIH-CoVnb-112 bound to SARS-CoV-2 RBD reveals a large contact surface area overlapping the angiotensin converting enzyme 2 (ACE2) binding site, which is largely unencumbered by the common RBD mutations. In an in vivo pilot study, we demonstrate effective reductions in weight loss, viral burden, and lung pathology in a Syrian hamster model of COVID-19 following nebulized delivery of NIH-CoVnb-112. These findings support the further development of NIH-CoVnb-112 as a potential adjunct preventative therapeutic for the treatment of SARS-CoV-2 infection.Abbreviations: ACE2 - angiotensin converting enzyme 2BSA - buried surface areaCDR - complementary determining regionRBD - receptor binding domainRBM - receptor-binding motifSARS-CoV-2 - severe acute respiratory syndrome coronavirus 2.


Asunto(s)
Anticuerpos Antivirales/metabolismo , Anticuerpos ampliamente neutralizantes/metabolismo , COVID-19/inmunología , Pulmón/patología , SARS-CoV-2/fisiología , Anticuerpos de Dominio Único/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Antivirales/inmunología , Sitios de Unión/genética , Anticuerpos ampliamente neutralizantes/inmunología , Cricetinae , Modelos Animales de Enfermedad , Humanos , Mesocricetus , Nebulizadores y Vaporizadores , Unión Proteica , Anticuerpos de Dominio Único/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Carga Viral
13.
bioRxiv ; 2022 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-35233570

RESUMEN

SARS-CoV-2 infection of host cells starts by binding of the Spike glycoprotein (S) to the ACE2 receptor. The S-ACE2 interaction is a potential target for therapies against COVID-19 as demonstrated by the development of immunotherapies blocking this interaction. Here, we present the commercially available VE607, comprised of three stereoisomers, that was originally described as an inhibitor of SARS-CoV-1. We show that VE607 specifically inhibits infection of SARS-CoV-1 and SARS-CoV-2 S-expressing pseudoviral particles as well as authentic SARS-CoV-2. VE607 stabilizes the receptor binding domain (RBD) in its "up" conformation. In silico docking and mutational analysis map the VE607 binding site at the RBD-ACE2 interface. The IC 50 values are in the low micromolar range for pseudoparticles derived from SARS-CoV-2 Wuhan/D614G as well as from variants of concern (Alpha, Beta, Gamma, Delta and Omicron), suggesting that VE607 has potential for the development of drugs against SARS-CoV-2 infections.

14.
Cell Rep ; 38(7): 110368, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-35123652

RESUMEN

Emerging evidence indicates that both neutralizing and Fc-mediated effector functions of antibodies contribute to protection against SARS-CoV-2. It is unclear whether Fc-effector functions alone can protect against SARS-CoV-2. Here, we isolated CV3-13, a non-neutralizing antibody, from a convalescent individual with potent Fc-mediated effector functions. The cryoelectron microscopy structure of CV3-13 in complex with the SARS-CoV-2 spike reveals that the antibody binds from a distinct angle of approach to an N-terminal domain (NTD) epitope that only partially overlaps with the NTD supersite recognized by neutralizing antibodies. CV3-13 does not alter the replication dynamics of SARS-CoV-2 in K18-hACE2 mice, but its Fc-enhanced version significantly delays virus spread, neuroinvasion, and death in prophylactic settings. Interestingly, the combination of Fc-enhanced non-neutralizing CV3-13 with Fc-compromised neutralizing CV3-25 completely protects mice from lethal SARS-CoV-2 infection. Altogether, our data demonstrate that efficient Fc-mediated effector functions can potently contribute to the in vivo efficacy of anti-SARS-CoV-2 antibodies.


Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéutico , COVID-19/terapia , Animales , Anticuerpos Antivirales/química , Citotoxicidad Celular Dependiente de Anticuerpos , COVID-19/mortalidad , COVID-19/prevención & control , COVID-19/transmisión , Modelos Animales de Enfermedad , Epítopos , Humanos , Inmunización Pasiva/mortalidad , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/metabolismo , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Ratones , Unión Proteica , Conformación Proteica , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Sueroterapia para COVID-19
15.
Chemosphere ; 287(Pt 2): 132150, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34826896

RESUMEN

A few studies reported the impact of mineral conductivity properties on contaminant-mineral-microbe interactions and microbial community structure changes in the interaction process. To fill the gap, conductive minerals (magnetite/hematite) and an insulative mineral (quartz) were introduced into Cr(VI) reduction systems to investigate the effect of mineral conductivity properties on Cr(VI) removal. Results showed that conductive minerals enhanced Cr(VI) reduction rate as compared to insulative minerals. Higher reduction percentage (>86%) was observed when both ERB (extracellular respiratory bacteria) and conductive minerals were presence than those with only minerals (<10%) or ERB (<55%), indicating a synergistic effect existed in this bio-remediation system. Moreover, surface elements detection manifested higher Fe-containing groups and Fe(III)-Cr(III) complexes covered on conductive minerals surface when ERB was present. Electrochemical data suggested that ERB facilitated the activity of electron transference on the surface of conductive minerals. Our results indicated that conductive minerals did act as an "electron shuttle" while insulative minerals increased adsorption sites to accelerate Cr(VI) reduction. 16S rRNA sequences results demonstrated that conductive minerals changed the microbial community structure and increased the diversity of the functional microbes including Pseudomonas spp. and Exiguobacterium spp. This work is of deep significance for better understanding the process of elements biogeochemical and elimination of pollutants.


Asunto(s)
Cromo , Compuestos Férricos , Anaerobiosis , Oxidación-Reducción , ARN Ribosómico 16S/genética
16.
Cell Rep ; 38(2): 110210, 2022 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-34971573

RESUMEN

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the "RBD-up" position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among ß-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

17.
Environ Res ; 204(Pt C): 112326, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34748776

RESUMEN

Along with rapid development of sulfate radicals-based advanced oxidation process, efficient, alternatively eco-friendly and cost-effective catalyst is of uppermost priority. However, expensive chemicals are used as source of metal in most of these catalysts, and lose sight of the abundant natural mineral resources on immediate surroundings. In this work, montmorillonite and hematite, two of abundantly natural minerals were utilized to prepare a persulfate catalyst (TMH@M) for sulfamethoxazole (SMX) degradation. The results indicated more than 91% of SMX was removed within 60 min in TMH@M/PS system. The degradation efficiency of SMX of TMH@M/PS combined system was impacted by SMX concentration, PS dosage and natural organic matters, and can remain stable in a certain concentration of HA/chelating agent and a wide pH range (3.01-9.06). Radical scavenging and EPR tests demonstrated 1O2, OH, and SO4- were major reactive oxygen species in the TMH@M/PS system, while the latter seems more important for degradation of SMX. The results of SEM-EDS, XRD and XPS conformed that low valence iron species (Fe0, Fe2+ and Fe3O4) on TMH@M surface are the main driving force behind PS activation to generate reactive species. Furthermore, the iron species on TMH@M surface were transformed during reaction, that in favor of mitigating metal leaching. This work presented a method based on ubiquitous natural minerals to prepare catalyst with excellent PS activate performance for organic wastewater treatment implying a new strategy in minerals utilization deeply and a promisingly alternative process for organic wastewater treatment based on mineral materials.


Asunto(s)
Sulfametoxazol , Contaminantes Químicos del Agua , Bentonita , Compuestos Férricos , Cinética , Oxidación-Reducción , Contaminantes Químicos del Agua/análisis
18.
bioRxiv ; 2021 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-34845451

RESUMEN

Soluble Angiotensin-Converting Enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses utilizing ACE2 as their receptor. Here, using structure-guided approaches, we developed divalent ACE2 molecules by grafting the extracellular ACE2-domain onto a human IgG1 or IgG3 (ACE2-Fc). These ACE2-Fcs harbor structurally validated mutations that enhance spike (S) binding and remove angiotensin enzymatic activity. The lead variant bound tightly to S, mediated in vitro neutralization of SARS-CoV-2 variants of concern (VOCs) with sub-nanomolar IC 50 and was capable of robust Fc-effector functions, including antibody-dependent-cellular cytotoxicity, phagocytosis and complement deposition. When tested in a stringent K18-hACE2 mouse model, it delayed death or effectively resolved lethal SARS-CoV-2 infection in a prophylactic or therapeutic setting utilizing the combined effect of neutralization and Fc-effector functions. These data confirm the utility of ACE2-Fcs as valuable agents in preventing and eliminating SARS-CoV-2 infection and demonstrate that ACE2-Fc therapeutic activity require Fc-effector functions.

19.
bioRxiv ; 2021 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-34790977

RESUMEN

There remains an unmet need for globally deployable, low-cost therapeutics for the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Previously, we reported on the isolation and in vitro characterization of a potent single-domain nanobody, NIH-CoVnb-112, specific for the receptor binding domain (RBD) of SARS-CoV-2. Here, we report on the molecular basis for the observed broad in vitro neutralization capability of NIH-CoVnb-112 against variant SARS-CoV-2 pseudoviruses, including the currently dominant Delta variant. The structure of NIH-CoVnb-112 bound to SARS-CoV-2 RBD reveals a large contact surface area overlapping the angiotensin converting enzyme 2 (ACE2) binding site, which is largely unencumbered by the common RBD mutations. In an in vivo pilot study, we demonstrate effective reductions in weight loss, viral burden, and lung pathology in a Syrian hamster model of COVID-19 following nebulized delivery of NIH-CoVnb-112. These findings support the further development of NIH-CoVnb-112 as a potential adjunct preventative therapeutic for the treatment of SARS-CoV-2 infection.

20.
bioRxiv ; 2021 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-34373853

RESUMEN

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here we elucidate the structural basis and mode of action for two potent SARS-CoV-2 Spike (S) neutralizing monoclonal antibodies CV3-1 and CV3-25 that remained effective against emerging variants of concern in vitro and in vivo. CV3-1 bound to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the "RBD-up" position and triggered potent shedding of the S1 subunit. In contrast, CV3-25 inhibited membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among ß-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

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