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1.
Int J Biol Macromol ; 265(Pt 1): 130790, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38484818

RESUMO

Phosphoramides, as a kind of high-efficient fire retardants, have been designed in many structures and endowed exceptional fire retardancy to polylactide (PLA). However, due to ignorance of the structure-property correlation, the effect of phosphoramides' structure on the fire retardancy and mechanical properties of PLA is still unclear. Herein, a series of biobased phosphoramides (phosphoramide (V1), linear polyphosphoramide (V2) and hyperbranched polyphosphamide (V3)) were designed and incorporated into PLA, and the structural effect of phosphoramides on the fire-retardant and mechanical properties of PLA was deeply researched. Among three kinds of phosphoramides, the hyperbranched polyphosphoramide is more effective than the corresponding linear polyphosphoramide and phosphoramide in improving the fire-retardant and anti-dripping properties of PLA, and only linear polyphosphoramide shows a positive effect in the mechanical strength of PLA. This work provides a feasible strategy for creating mechanically robust and fire-retardant polymer composites by molecularly tailoring the structure of fire retardants and uncovering their structure-property relationship.


Assuntos
Retardadores de Chama , Fosforamidas , Poliésteres
2.
Int J Biol Macromol ; 262(Pt 2): 130144, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38360228

RESUMO

The phosphoramide phosphorus ester phosphate ammonium (PPEPA) flame retardant was synthesized by phosphorus oxychloride and ethanolamine, and its structure was characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy (FTIR). Cotton textiles treated with 20 wt% PPEPA (CT-PPEPA3) would have high durability and flame retardance. The limiting oxygen index (LOI) of CT-PPEPA3 was found to be 46.5 %, while after undergoing 50 laundering cycles (LCs) following the AATCC 61-2013 3 A standard, the LOI only decreased to 31.4 %. Scanning electron microscopy and X-ray diffraction analyses suggested the penetration of PPEPA molecules into the interior of cotton fibers, resulting in a minor alteration of the cellulose crystal structure. The excellent durability, FTIR, and energy-dispersive X-ray of CT-PPEPA3 provided evidence for the formation of -N-P(=O)-O-C- and -O-P(=O)-O-C- covalent bonds between the PPEPA molecules and cellulose. The -N-P(=O)-O-C- bond exhibited a p-π conjugation effect, leading to enhanced stability and improved durability of the flame-retardant cotton textiles. Vertical flame, thermogravimetric, and cone calorimetry tests demonstrated that the CT-PPEPA3 underwent condensed-phase and synergistic flame retardation. Additionally, these finished cotton textiles retained adequate breaking strength and softness, making them suitable for various applications. In conclusion, the incorporation of the -N-P(=O)-ONH4 group into the phosphorus ester phosphate ammonium flame retardant demonstrated effective enhancement of the fire resistance and durability of treated cotton textiles.


Assuntos
Compostos de Amônio , Retardadores de Chama , Fósforo , Fosfatos , Fosforamidas , Têxteis , Fibra de Algodão , Celulose
3.
Int J Mol Sci ; 25(1)2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38203788

RESUMO

Detection of the Kirsten rat sarcoma gene (KRAS) mutational status is an important factor for the treatment of various malignancies. The most common KRAS-activating mutations are caused by single-nucleotide mutations, which are usually determined by using PCR, using allele-specific DNA primers. Oligonucleotide primers with uncharged or partially charged internucleotide phosphate modification have proved their ability to increase the sensitivity and specificity of various single nucleotide mutation detection. To enhance the specificity of single nucleotide mutation detection, the novel oligonucleotides with four types of uncharged and partially charged internucleotide phosphates modification, phosphoramide benzoazole (PABA) oligonucleotides (PABAO), was used to prove the concept on the KRAS mutation model. The molecular effects of different types of site-specific PABA modification in a primer or a template on a synthesis of full-length elongation product and PCR efficiency were evaluated. The allele-specific PCR (AS-PCR) on plasmid templates showed a significant increase in analysis specificity without changes in Cq values compared with unmodified primer. PABA modification is a universal mismatch-like disturbance, which can be used for single nucleotide polymorphism discrimination for various applications. The molecular insights of the PABA site-specific modification in a primer and a template affect PCR, structural features of four types of PABAO in connection with AS-PCR results, and improvements of AS-PCR specificity support the further design of novel PCR platforms for various biological targets testing.


Assuntos
Ácido 4-Aminobenzoico , Amidas , Oligonucleotídeos , Fosforamidas , Ácidos Fosfóricos , Oligonucleotídeos/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas p21(ras) , Fosfatos , Nucleotídeos , Azóis , Reação em Cadeia da Polimerase
4.
Expert Opin Investig Drugs ; 33(1): 9-17, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38265202

RESUMO

INTRODUCTION: Chronic hepatitis C virus (HCV) persists as a public health concern worldwide. Consequently, optimizing HCV therapy remains an important objective. While current therapies are generally highly effective, advanced antiviral agents are needed to maximize cure rates with potentially shorter treatment durations in a broader patient population, particularly those patients with advanced diseases who remain difficult to treat. AREAS COVERED: This review summarizes the in vitro anti-HCV activity, preclinical pharmacological properties of bemnifosbuvir (BEM, AT-527), a novel prodrug that is metabolically converted to AT-9010, the active guanosine triphosphate analogue that potently and selectively inhibits several viral RNA polymerases, including the HCV NS5B polymerase. Results from clinical proof-of-concept and phase 2 combination studies are also discussed. EXPERT OPINION: BEM exhibits potent pan-genotype activity against HCV, and has favorable safety, and drug interaction profiles. BEM is approximately 10-fold more potent than sofosbuvir against HCV genotypes (GT) tested in vitro. When combined with a potent NS5A inhibitor, BEM is expected to be a promising once-daily oral antiviral for chronic HCV infection of all genotypes and fibrosis stages with potentially short treatment durations.


Assuntos
Guanosina Monofosfato/análogos & derivados , Hepatite C Crônica , Hepatite C , Fosforamidas , Humanos , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Antivirais/efeitos adversos , Sofosbuvir/farmacologia , Sofosbuvir/uso terapêutico , Hepatite C/tratamento farmacológico , Genótipo , Quimioterapia Combinada , Proteínas não Estruturais Virais
5.
Biochem Biophys Res Commun ; 693: 149390, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38128245

RESUMO

In this work, we for the first time conducted a detailed study on the structure, dynamics, and hybridization properties of N-benzimidazole group-bearing phosphoramide benzoazole oligonucleotides (PABAOs) that we developed recently. By circular dichroism we established that the introduction of the modifications does not disrupt the B conformation of the DNA double helix. The formation of complexes is approximated by a two-state model. Complexes of PABAOs with native oligodeoxriboynucleotides form efficiently, and the introduction of such modifications reduces thermal stability of short duplexes (8-10 bp) by ∼5°Ð¡ per modification. Using UV-spectroscopy analysis, a neutral charge of the phosphate residue modified by the N-benzimidazole moiety in the pH range of 3-9.5 was found. The results confirm possible usefulness of PABAOs for both basic research and biomedical applications.


Assuntos
Oligonucleotídeos , Fosforamidas , Oligonucleotídeos/química , Desnaturação de Ácido Nucleico , DNA/química , Hibridização de Ácido Nucleico , Conformação de Ácido Nucleico , Termodinâmica , Dicroísmo Circular
6.
J Agric Food Chem ; 71(13): 5261-5274, 2023 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-36962004

RESUMO

The acephate-degrading microbes that are currently available are not optimal. In this study, Burkholderia sp. A11, an efficient degrader of acephate, presented an acephate-removal efficiency of 83.36% within 56 h (100 mg·L-1). The A11 strain has a broad substrate tolerance and presents a good removal effect in the concentration range 10-1600 mg·L-1. Six metabolites from the degradation of acephate were identified, among which the main products were methamidophos, acetamide, acetic acid, methanethiol, and dimethyl disulfide. The main degradation pathways involved include amide bond breaking and phosphate bond hydrolysis. Moreover, strain A11 successfully colonized and substantially accelerated acephate degradation in different soils, degrading over 90% of acephate (50-200 mg·kg-1) within 120 h. 16S rDNA sequencing results further confirmed that the strain A11 gradually occupied a dominant position in the soil microbial communities, causing slight changes in the diversity and composition of the indigenous soil microbial community structure.


Assuntos
Burkholderia , Inseticidas , Compostos Organotiofosforados , Biodegradação Ambiental , Inseticidas/química , Compostos Organofosforados , Compostos Organotiofosforados/química , Fosforamidas , Solo , Burkholderia/metabolismo
7.
Curr Med Chem ; 30(30): 3486-3503, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36305155

RESUMO

BACKGROUND: Graphene oxide (GO)-based systems are among the drug delivery systems and have drawn a lot of interest in the field of medicine. METHODS: In this work, two novel phosphoramides with the formulas of (NHCHCH2C(CH3)2NHC(CH3)2CH2P(S)(OEt)2 (L1) and (NHCHCH2C(CH3)2 NHC (CH3)2CH2P (O) (NHC6H5) (OC5H6) (L2) were synthesized and characterized by spectroscopic methods. Then, graphene oxide (GO) was functionalized by L1 and L2. FT-IR, XRD, FE- SEM/ MAP, and Zeta potential analyses were applied to confirm the synthesis of phosphoramide-functionalized graphene oxides (GO-L1 and GO-L2). Cytotoxicity of synthesized compounds was evaluated against breast cancer cell line (SK-BR-3) using MTT assay. Moreover, the flow cytometry assay was performed to evaluate the cell death mechanisms. RESULTS: The results showed that GO-L1 and GO-L2 had a more inhibitory effect against cancer cells than that of L1 and L2, and GO-L2 showed the highest cytotoxicity with an IC50 value of 38.13 µg/ml. Quantum calculations were employed to optimize structures. HOMO and LUMO energy values and physical adsorption of synthesized compounds were obtained by the DMol3 module in the Material Studio 2017. The docking studies were used to investigate the binding of L1, L2, GO-L1, and GO-L2 to DNA polymerase IIα. CONCLUSION: Anticancer activity of phosphoramide compounds was increased after attachment on the GO surface, and the docking studies' results were in good accordance with the experimental cytotoxicity results.


Assuntos
Grafite , Humanos , Grafite/química , Fosforamidas , Óxidos/farmacologia , Óxidos/química , Espectroscopia de Infravermelho com Transformada de Fourier
8.
J Mol Model ; 28(10): 316, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36107268

RESUMO

Environmental contamination by pesticides is a recurrent problem, and a way to minimize its impacts and provide the reduction of contaminants already in the environment is a challenge. In this context, porous materials such as metal-organic frameworks (MOFs) have gained prominence. MOFs can carry the pesticide when physically or chemically interacting with its pore sites, enabling pesticide capture. However, evaluating the best MOF to maximize the process is an important step that can be performed under computer simulation. This work used grand canonical Monte Carlo simulations to assess the interaction between glyphosate, atrazine, acephate, and dichlorodiphenyltrichloroethane pesticides with the structures of IRMOF-1, IRMOF-8, IRMOF-10, and IRMOF-16. These MOFs present several organic unit types, which generate different pore volumes with similar chemical environment. For glyphosate, atrazine, and acephate, a direct relationship was shown between the pore volume and the amount of captured pesticide, which is a direct contribution from the strong interaction between the pesticides. Higher pore volumes maximize glyphosate, atrazine, and acephate capture. Otherwise, for dichlorodiphenyltrichloroethane, the larger the pore volume, the smaller the amount of pesticide is loaded. The interaction between all pesticides and IRMOFs is mainly governed by van der Waals contribution, being more pronounced for glyphosate, atrazine, and acephate molecules.


Assuntos
Atrazina , Estruturas Metalorgânicas , Praguicidas , Simulação por Computador , Eletrônica , Estruturas Metalorgânicas/química , Compostos Organotiofosforados , Fosforamidas
9.
J Econ Entomol ; 115(5): 1693-1702, 2022 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-36099406

RESUMO

Foliar-applied insecticide treatments may be necessary to manage thrips in cotton (Gossypium hirsutum L.) under severe infestations or when at-planting insecticide seed treatments do not provide satisfactory protection. The most common foliar-applied insecticide is acephate. Field observations in Tennessee suggest that the performance of acephate has declined. Thus, the first objective was to perform leaf-dip bioassays to assess if tobacco thrips, Frankliniella fusca (Hinds) (Thysanoptera: Thripidae), in cotton production regions have evolved resistance to foliar-applied insecticides. A second objective was to assess the performance of commonly applied foliar insecticides for managing thrips in standardized field trials in Arkansas, Tennessee, Mississippi, and Texas. For both objectives, several insecticides were evaluated including acephate, dicrotophos, dimethoate, lambda-cyhalothrin, imidacloprid, and spinetoram. Field trials and bioassays were completed from 2018 to 2021. Dose-response bioassays with acephate were performed on tobacco thrips field populations and a susceptible laboratory population. Bioassay results suggest that tobacco thrips have developed resistance to acephate and other organophosphate insecticides; however, this resistance seems to be most severe in Arkansas, Tennessee, and the Delta region of Mississippi. Resistance to other classes of insecticides were perhaps even more evident in these bioassays. The performance of these insecticides in field trials was variable, with tobacco thrips only showing consistent signs of resistance to lambda-cyhalothrin. However, it is evident that many populations of tobacco thrips are resistant to multiple classes of insecticides. Further research is needed to determine heritability and resistance mechanism(s).


Assuntos
Inseticidas , Tisanópteros , Animais , Bioensaio , Dimetoato , Gossypium , Inseticidas/farmacologia , Nitrilas , Compostos Organotiofosforados , Fosforamidas , Piretrinas , Estados Unidos
10.
ACS Nano ; 16(9): 15141-15154, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-35977379

RESUMO

Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants continue to emerge. For example, some early therapies (e.g., antibodies) have experienced markedly decreased efficacy. Due to a growing concern of future drug resistant variants, current drug development strategies are seeking to find effective drug combinations. In this study, we used IDentif.AI, an artificial intelligence-derived platform, to investigate the drug-drug and drug-dose interaction space of six promising experimental or currently deployed therapies at various concentrations: EIDD-1931, YH-53, nirmatrelvir, AT-511, favipiravir, and auranofin. The drugs were tested in vitro against a live B.1.1.529 (Omicron) virus first in monotherapy and then in 50 strategic combinations designed to interrogate the interaction space of 729 possible combinations. Key findings and interactions were then further explored and validated in an additional experimental round using an expanded concentration range. Overall, we found that few of the tested drugs showed moderate efficacy as monotherapies in the actionable concentration range, but combinatorial drug testing revealed significant dose-dependent drug-drug interactions, specifically between EIDD-1931 and YH-53, as well as nirmatrelvir and YH-53. Checkerboard validation analysis confirmed these synergistic interactions and also identified an interaction between EIDD-1931 and favipiravir in an expanded range. Based on the platform nature of IDentif.AI, these findings may support further explorations of the dose-dependent drug interactions between different drug classes in further pre-clinical and clinical trials as possible combinatorial therapies consisting of unmodified and nanomedicine-enabled drugs, to combat current and future COVID-19 strains and other emerging pathogens.


Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Amidas , Inteligência Artificial , Auranofina , Guanosina Monofosfato/análogos & derivados , Humanos , Fosforamidas , Pirazinas
11.
Ned Tijdschr Geneeskd ; 1662022 07 21.
Artigo em Holandês | MEDLINE | ID: mdl-36036702

RESUMO

The anti-inflammatory agents dexamethasone (corticosteroid), and tocilizumab and sarilumab (IL6-inhibitors) are effective in the treatment of late COVID-19. Other anti-inflammatory agents, like anakinra (IL1-inhibitor), baricitinib and tofacitinib (JAK-inhibitors) and lenzilumab (GM-CSF-inhibitor) have also shown positive results in late COVID-19. For the treatment of early COVID-19, the inhalation corticosteroid budesonide is regarded as an off-label treatment option. Virus-inhibitors, like remdesivir, molnupiravir and nirmatrelvir/ritonavir decrease the risk of hospitalization and the development of severe COVID-19 by patients with early symptoms. Monoclonal antibodies have shown limited or no efficacy against the omicron-variant of SARS-CoV-2. Fluvoxamine, l-arginine, AT-527 and ensovibep are considered as potential promising new therapies for the treatment of early COVID-19.


Assuntos
Tratamento Farmacológico da COVID-19 , Corticosteroides , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Guanosina Monofosfato/análogos & derivados , Humanos , Fosforamidas , Proteínas Recombinantes de Fusão , SARS-CoV-2
12.
Int J Mol Sci ; 23(16)2022 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-36012388

RESUMO

New insights into the interactions between nanopesticides and edible plants are required in order to elucidate their impacts on human health and agriculture. Nanopesticides include formulations consisting of organic/inorganic nanoparticles. Drosophila melanogaster has become a powerful model in genetic research thanks to its genetic similarity to mammals. This project mainly aimed to generate new evidence for the toxic/genotoxic properties of different nanopesticides (a nanoemulsion (permethrin nanopesticides, 20 ± 5 nm), an inorganic nanoparticle as an active ingredient (copper(II) hydroxide [Cu(OH)2] nanopesticides, 15 ± 6 nm), a polymer-based nanopesticide (acephate nanopesticides, 55 ± 25 nm), and an inorganic nanoparticle associated with an organic active ingredient (validamycin nanopesticides, 1177 ± 220 nm)) and their microparticulate forms (i.e., permethrin, copper(II) sulfate pentahydrate (CuSO4·5H2O), acephate, and validamycin) widely used against agricultural pests, while also showing the merits of using Drosophila-a non-target in vivo eukaryotic model organism-in nanogenotoxicology studies. Significant biological effects were noted at the highest doses of permethrin (0.06 and 0.1 mM), permethrin nanopesticides (1 and 2.5 mM), CuSO4·5H2O (1 and 5 mM), acephate and acephate nanopesticides (1 and 5 mM, respectively), and validamycin and validamycin nanopesticides (1 and 2.5 mM, respectively). The results demonstrating the toxic/genotoxic potential of these nanopesticides through their impact on cellular internalization and gene expression represent significant contributions to future nanogenotoxicology studies.


Assuntos
Cobre , Permetrina , Animais , Cobre/toxicidade , Drosophila , Drosophila melanogaster , Humanos , Hidróxidos , Inositol/análogos & derivados , Mamíferos , Compostos Organotiofosforados , Permetrina/toxicidade , Fosforamidas
13.
Int J Biol Macromol ; 219: 558-570, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-35907467

RESUMO

Two kinds of phosphoramide derivatives containing one (POFA) or two (BPOFA) phosphoramide bonds were synthesized using diphenylphosphinic chloride, phenylphosphonic dichloride and furfurylamine, respectively. The flame retardancy, thermal degradation and crystallization behaviors of polylactic acid (PLA)/POFA and PLA/BPOFA blends were investigated using the limiting oxygen index (LOI), UL-94 vertical burning tests, cone calorimeter tests, thermogravimetric analysis and differential scanning calorimetry. A small amount of 1.0 wt% BPOFA increases the LOI of PLA from 20.4 vol% to 28.0 vol% and achieves the UL-94 V0 rating, while 7.0 wt% POFA is needed to achieve the UL-94 V0 rating indicating that the PLA/BPOFA has better flame retardancy than that of PLA/POFA. Both POFA and BPOFA decrease the amount of flammable gaseous compounds and play positive roles in transesterification of PLA. More importantly, BPOFA is easier to catalyze the degradation of PLA and improve UL-94 rating by melting-away mode. Moreover, the BPOFA accelerates the crystallization rate and thus improves the crystallinity of PLA, while POFA does not show a positive effect on crystallization behaviors of PLA.


Assuntos
Retardadores de Chama , Fosforamidas , Cloretos , Cristalização , Oxigênio , Poliésteres/química
14.
Talanta ; 247: 123550, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35671579

RESUMO

For the development of selective and sensitive chemical sensors, we have developed a new family of poly(ether-phosphoramide) polymers. These polymers were obtained with satisfactory yields by nucleophilic aromatic polycondensation using isosorbide as green resources, and bisphenol A with two novel difluoro phosphinothioic amide monomers. Unprecedented, the thiophosphorylated aminoheterocycles monomers, functionalized with two heterocyclic amine, N-methylpiperazine and morpholine were successfully obtained by nucleophilic substitution reaction of P(S)-Cl compound. The resulting polymers were characterized by different analytical techniques (NMR, MALDI-ToF MS, GPC, DSC, and ATG). The resulting partially green polymers, having tertiary phosphine sulfide with P-N side chain functionalities along the main chain of polymers are the sensitive film at the surface of a gold electrode for the impedimetric detection of Cd, Ni, Pb and Hg. The bio-based poly(ether-phosphoramide) functionalized with N-methylpiperazine modified sensor showed better analytical performance than petrochemical based polymers for the detection of Ni2+. A detection limit of 50 pM was obtained which is very low compared to the previously published electrochemical sensors for nickel detection.


Assuntos
Técnicas Biossensoriais , Níquel , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Eletrodos , Éter , Éteres , Limite de Detecção , Níquel/química , Fosforamidas , Polímeros/química , Sulfetos
15.
J Sep Sci ; 45(10): 1806-1817, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35261148

RESUMO

Acephate is widely used in crops as racemate. However, the enantioselective dissipation of acephate enantiomers has not been investigated in pakchoi. A sensitive and effective approach was established for determining residues of acephate and its highly toxic metabolite methamidophos enantiomers by supercritical fluid chromatography tandem mass spectrometry. Baseline separations for their enantiomers were achieved by using a Chiralcel OD-H column. The optimal chromatographic conditions were obtained as follows: CO2 /ethanol (95/5) as mobile phase; flow rate, 3.0 mL/min; column temperature, 40°C. The mean recoveries (RSDs) of analytes were in the range of 77-83.1% (6.1-9.9%), 75.4-87.5% (9.3-13.2%), and 81.5-84.2% (7.1-13.4%) at three fortification levels (0.005, 0.05, and 0.5 mg/kg for each enantiomer) for interday assay (n = 18). The method was used to evaluate the enantioselective dissipation of acephate and methamidophos in pakchoi. S-acephate dissipated faster than R-acephate, while the concentration of R-methamidophos was higher than that of S-methamidophos during the entire study period. The results indicated that the R-enantiomer of acephate and methamidophos was preferentially enriched in pakchoi. The established analysis approach and the study data provided useful information for the rational use of acephate in agriculture.


Assuntos
Cromatografia com Fluido Supercrítico , Inseticidas , Inseticidas/análise , Compostos Organotiofosforados , Fosforamidas , Estereoisomerismo , Espectrometria de Massas em Tandem/métodos
16.
Nat Commun ; 13(1): 621, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110538

RESUMO

The guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, AT-527 is converted into its triphosphate form, AT-9010, that presumably targets the viral RNA-dependent RNA polymerase (RdRp, nsp12), for incorporation into viral RNA. Here we report a 2.98 Å cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-nsp82-RNA complex, showing AT-9010 bound at three sites of nsp12. In the RdRp active-site, one AT-9010 is incorporated at the 3' end of the RNA product strand. Its modified ribose group (2'-fluoro, 2'-methyl) prevents correct alignment of the incoming NTP, in this case a second AT-9010, causing immediate termination of RNA synthesis. The third AT-9010 is bound to the N-terminal domain of nsp12 - known as the NiRAN. In contrast to native NTPs, AT-9010 is in a flipped orientation in the active-site, with its guanine base unexpectedly occupying a previously unnoticed cavity. AT-9010 outcompetes all native nucleotides for NiRAN binding, inhibiting its nucleotidyltransferase activity. The dual mechanism of action of AT-527 at both RdRp and NiRAN active sites represents a promising research avenue against COVID-19.


Assuntos
Antivirais/química , Antivirais/farmacologia , Guanosina Monofosfato/análogos & derivados , Fosforamidas/química , Fosforamidas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , SARS-CoV-2/enzimologia , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , COVID-19/virologia , Microscopia Crioeletrônica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Guanosina Monofosfato/química , Guanosina Monofosfato/farmacologia , Humanos , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Proteínas Virais/genética
17.
Bioorg Chem ; 120: 105617, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35065467

RESUMO

In this study, two new phosphoramides containing imidazolidine; diphenyl (2-imidazolidinone-1-yl)phosphonate (DIOP) and diphenyl (2-Imidazolidinethione -1-yl)phosphonate (DITP) as cytotoxic agents, were synthesized and characterized by using IR, 1H NMR, 13C NMR, 31P NMR, Mass spectroscopy and elemental analysis. The target products were obtained in moderate to good yields (69-86%) by using the time (3 h) and solvent (MeCN). The crystal structure of DIOP was investigated using X-ray crystallography. The main non-covalent intermolecular interactions were also studied by Hirshfeld surface analysis and fingerprint plots. The anticancer and growth inhibitory activities of the synthesized compounds were investigated against human breast cancer cell line MDA-MB-231 using MTT assay; DITP was found to be a better cytotoxic agent than DIOP. The cytotoxicity results were supported by a molecular docking study and in order to know the structure-activity relationship (SAR) of synthesized compounds, the values of HOMO and LUMO energies, dipole moments, hardness, softness, and electrophilicity index were investigated computationally by DFT method. These results were in good accordance with those of in vitro investigation and molecular docking study.


Assuntos
Antineoplásicos , Imidazolidinas , Organofosfonatos , Antineoplásicos/química , Antineoplásicos/farmacologia , Citotoxinas , Humanos , Imidazolidinas/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosforamidas
18.
Photosynth Res ; 152(1): 13-22, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34988868

RESUMO

Chlorophyll f is a new type of chlorophyll isolated from cyanobacteria. The absorption and fluorescence characteristics of chlorophyll f permit these oxygenic-photosynthetic organisms to thrive in environments where white light is scarce but far-red light is abundant. To explore the ligand properties of chlorophyll f and its energy transfer profiles we established two different in vitro reconstitution systems. The reconstituted peridinin-chlorophyll f protein complex (chlorophyll f-PCP) showed a stoichiometry ratio of 4:1 between peridinin and chlorophyll f, consistent with the peridinin:chlorophyll a ratio from native PCP complexes. Using emission wavelength at 712 nm, the excitation fluorescence featured a broad peak at 453 nm and a shoulder at 511 nm confirming energy transfer from peridinin to chlorophyll f. In addition, by using a synthetic peptide mimicking the first transmembrane helix of light-harvesting chlorophyll proteins of plants, we report that chlorophyll f, similarly to chlorophyll b, did not interact with the peptide contrarily to chlorophyll a, confirming the accessory role of chlorophyll f in photosystems. The binding of chlorophyll f, even in the presence of chlorophylls a and b, by PCP complexes shows the flexibility of chlorophyll-protein complexes and provides an opportunity for the introduction of new chlorophyll species to extend the photosynthetic spectral range.


Assuntos
Dinoflagelados , Clorofila/análogos & derivados , Clorofila/metabolismo , Clorofila A/metabolismo , Dinoflagelados/metabolismo , Guanosina Monofosfato/análogos & derivados , Fosforamidas
19.
J Hazard Mater ; 426: 127841, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34844804

RESUMO

The microbial degradation of acephate in pure cultures has been thoroughly explored, but synergistic metabolism at the community level has rarely been investigated. Here, we report a novel microbial consortium, ZQ01, capable of effectively degrading acephate and its toxic product methamidophos, which can use acephate as a source of carbon, phosphorus and nitrogen. The degradation conditions with consortium ZQ01 were optimized using response surface methodology at a temperature of 34.1 °C, a pH of 8.9, and an inoculum size of 2.4 × 108 CFU·mL-1, with 89.5% of 200 mg L-1 acephate degradation observed within 32 h. According to the main products methamidophos, acetamide and acetic acid, a novel degradation pathway for acephate was proposed to include hydrolysis and oxidation as the main pathways of acephate degradation. Moreover, the bioaugmentation of acephate-contaminated soils with consortium ZQ01 significantly enhanced the removal rate of acephate. The results of the present work demonstrate the potential of microbial consortium ZQ01 to degrade acephate in water and soil environments, with a different and complementary acephate degradation pathway.


Assuntos
Consórcios Microbianos , Fosforamidas , Biodegradação Ambiental , Compostos Organotiofosforados , Solo , Microbiologia do Solo
20.
Sci Total Environ ; 806(Pt 4): 150863, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34626633

RESUMO

Enantioselective metabolism of chiral pesticide in plants is very important. In vitro system has become an effective means to study the metabolism of pesticides in plants, but the study on the metabolism of chiral pesticides has not been reported. This work compared the enantiomer metabolic behavior of acephate and its metabolite methamidophos between tea cell suspensions and excised tea stem with leaves. (±)-Acephate could be absorbed and transferred well to top leaves by the cut end of excised stem after 24 h. (±)-Methamidophos was derived from the metabolism of (±)-acephate in tea plants at 3-5% in leaves and 2-3% in stems at 216 h. The content of (+)-methamidophos was 1.5 times higher than that of (-)-methamidophos in excised leaves. Though both (±)-acephate and (±)-methamidophos could be metabolized well by cell suspension, (±)-acephate and (±)-methamidophos was non-enantioselectively metabolized in cell suspension. It was shown that using the excised tea stem with leaves for chiral pesticide metabolism studies was much closer to intact plant than cell suspensions. This result also established an effective and easily available in vitro metabolic model for the study of enantioselective metabolism of chiral contaminants from environment.


Assuntos
Camellia sinensis , Inseticidas , Inseticidas/análise , Compostos Organotiofosforados , Fosforamidas , Folhas de Planta/química , Estereoisomerismo , Suspensões , Chá
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