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1.
BMC Infect Dis ; 22(1): 17, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983415

RESUMO

BACKGROUND: Concerns regarding potential toxicity and drug-drug interactions during long-term treatment with three-drug active antiretroviral therapy (ART) regimens have been attracting increasing attention. We aimed to evaluate the efficacy and safety of dolutegravir (DTG) plus lamivudine (3TC) in ART-naive adults in China. METHODS: This prospective observational cohort study enrolled HIV-naive inpatients treated with DTG + 3TC (2DR arm) or efavirenz (EFV) plus tenofovir disoproxil fumarate (TDF) and 3TC (3DR arm). There were no limits on baseline viral load. Inflammatory biomarkers were also investigated in the 2DR arm. RESULTS: Between September 2019 and January 2020, 27 patients treated with DTG + 3TC and 28 patients treated with EFV + TDF + 3TC were enrolled in the study. At week 12, the proportion of patients with viral loads < 50 copies/mL in the 2DR arm was 81.5% (22/27) compared with 53.6% (15/28) in the 3DR arm (p < 0.01). At week 24, the proportion of patients with viral loads < 50 copies/mL in the 2DR arm was 100% (26/26) compared with 83.3% (20/24) in the 3DR arm (p < 0.05). Mean changes in CD4 cell counts from baseline at week 12 were 125.46 cells/µL in the 2DR arm and 41.20 cells/µL in the 3DR arm (p < 0.05). Mean changes in CD4 cell counts from baseline at week 24 were 209.68 cells/µL in the 2DR arm and 73.28 cells/µL in the 3DR arm (p < 0.05). CONCLUSIONS: DTG + 3TC achieved virologic suppression more rapidly than EFV + TDF + 3TC after 12 and 24 weeks. DTG + 3TC could represent an optimal regimen for advanced patients. Clinical Trial Registration ChiCTR1900027640 (22/November/2019).


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Alcinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Ciclopropanos , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis , Humanos , Lamivudina/uso terapêutico , Oxazinas , Piperazinas , Estudos Prospectivos , Piridonas , Tenofovir/uso terapêutico
2.
Methods Mol Biol ; 2370: 323-329, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34611878

RESUMO

The sialome or display of sialic acids on the surface of human immune cells can vary according to immune response and activation state. Here, human peripheral blood mononuclear cells (PBMCs) were isolated and activated with anti-CD3 antibody and the cell surface sialome was quantified using a combination of click chemistry, confocal microscopy and flow cytometry techniques. Carbohydrate click chemistry was used to detect and measure the incorporation of an azido-m65odified sialic acid precursor molecule, N-acetylmannosamine (ManNaz) sugar into the PBMC surface sialome. Incorporation of sialic acid into the PBMC glycocalyx was visualized using copper-catalyzed click conjugation of Alexa 488 alkyne and confocal microscopy and further quantified using flow cytometry. The use of these methods indicate that regulating the sialome content on the surface of activated immune cells may be monitored during immunomodulatory responses and anti-inflammatory therapies.


Assuntos
Leucócitos Mononucleares , Ácido N-Acetilneuramínico , Ácidos Siálicos , Alcinos , Química Click , Humanos , Ácidos Siálicos/metabolismo
3.
Methods Mol Biol ; 2412: 35-44, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34918240

RESUMO

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, well-known as "click" reaction, is widely used in organic synthesis, medicinal chemistry, and polymer science for the conjugation of molecular entities of all sizes. In this protocol, B-cell epitope J8, derived from group A Streptococcus (GAS) M protein, and universal T-helper epitope PADRE were conjugated to poly(methyl acrylate) (PMA) to form a self-assembled nanoparticle vaccine candidate (PMA-P-J8). The vaccine construct was orally administered to mice in a single dose of 30 µg, resulting in the production of a high number of serum (IgG) and salivary (IgA) antibodies.


Assuntos
Química Click , Alcinos , Animais , Azidas , Catálise , Reação de Cicloadição , Imunização , Camundongos , Peptídeos , Polímeros , Vacinas Conjugadas , Vacinas de Subunidades
4.
J Colloid Interface Sci ; 606(Pt 2): 1179-1192, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34487937

RESUMO

Many drugs and drug candidates are poorly water-soluble. Intestinal fluids play an important role in their solubilization. However, the interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz (EFV) as model drug, the triblock copolymers Pluronic® F-127 (PF127) and poly(2-oxazoline) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was however observed if EFV was involved. PF127/EFV formulations in FeSSIF showed concentration dependent aggregation with separate colloids at low formulation concentrations, a merging of individual particles at the solubility limit of EFV in FeSSIF and joint aggregates above this concentration. In the case of pOx/pOzi/EFV formulations, coincident diffusion coefficients for pOx/pOzi, lipids and EFV indicate joint aggregates across the studied concentration range. This demonstrates that separate evaluation of polymers and drugs in biorelevant media is not sufficient and their mixtures need to be studied to learn about concentration and composition dependent behaviour.


Assuntos
Benzoxazinas , Poloxâmero , Alcinos , Ciclopropanos , Excipientes , Solubilidade
5.
N Engl J Med ; 385(27): 2531-2543, 2021 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-34965338

RESUMO

BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1 , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Administração Oral , Adolescente , Alcinos/uso terapêutico , Antirretrovirais/efeitos adversos , Benzoxazinas/uso terapêutico , Criança , Pré-Escolar , Colesterol/sangue , Ciclopropanos/uso terapêutico , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , HIV-1/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Oxazinas/administração & dosagem , Oxazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Carga Viral/efeitos dos fármacos
6.
Biochemistry ; 60(51): 3879-3886, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34910871

RESUMO

The reliance of biocatalysis on plant-derived carbon for the synthesis of fuels and chemicals places it in direct competition with food production for resources. A potential solution to this problem is development of a metabolic link between alternative carbon sources and bacterial metabolism. Acetylenecarboxylic acid, which can be synthesized from methane and carbon dioxide, could enable this connection. It was previously shown that the enzyme Cg10062 catalyzes hydration of acetylenecarboxylate to afford malonate semialdehyde. Subsequent hydration-dependent decarboxylation to form acetaldehyde (81%), which was also observed, limits its biocatalytic usefulness. Several Cg10062 variants including E114Q and E114D do not catalyze decarboxylation and provide malonate semialdehyde as the sole product, albeit with substantially reduced catalytic activity. To identify an efficient enzyme capable of catalyzing acetylenecarboxylate hydration without decarboxylation, we undertook a mechanistic investigation of Cg10062 using mutagenesis, kinetic characterization, and X-ray crystallography. Cg10062 is a member of the tautomerase superfamily of enzymes, characterized by their ß-α-ß protein fold and an N-terminal proline residue situated at the center of the enzyme active site. Along with Pro-1, five additional active site residues (His-28, Arg-70, Arg-73, Tyr-103, and Glu-114) are required for Cg10062 activity. Incubation of crystals of four catalytically slow variants of Cg10062 with acetylenecarboxylate resulted in atomic resolution structures of Pro-1 bound to a complete set of intermediates, fully elaborating the detailed mechanism of the enzyme and establishing the process to involve covalent catalysis. Further, the intermediate-bound E114D structure explains the mechanism governing decarboxylation suppression. Together, these studies provide the most detailed picture of the catalytic mechanism of a tautomerase enzyme to date.


Assuntos
Alcinos/metabolismo , Bactérias/metabolismo , Ácidos Graxos Insaturados/metabolismo , Hidrolases/metabolismo , Substituição de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biocatálise , Biomassa , Ciclo do Carbono , Domínio Catalítico/genética , Corynebacterium glutamicum/enzimologia , Corynebacterium glutamicum/genética , Hidrolases/química , Hidrolases/genética , Cinética , Modelos Biológicos , Modelos Moleculares , Mutagênese Sítio-Dirigida
7.
Anal Chim Acta ; 1187: 339138, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34753566

RESUMO

The analytical performance of the microarray technique in screening the affinity and reactivity of molecules towards a specific target, is highly affected by the coupling chemistry adopted to bind probes to the surface. However, the surface functionality limits the biomolecules that can be attached to the surface to a single type of molecule, thus forcing the execution of separate analyses to compare the performance of different species in recognizing their targets. Here we introduce a new N, N-dimethylacrylamide-based polymeric coating, bearing simultaneously different functionalities (N-acryloyloxysuccinimide and azide groups) to allow an easy and straightforward method to co-immobilize proteins and oriented peptides on the same substrate. The bi-functional copolymer has been obtained by partial post polymerization modification of the functional groups of a common precursor. A NMR characterization of the copolymer was conducted to quantify the percentage of NAS that has been transformed into azido groups. The polymer was used to coat surfaces onto which both native antibodies and alkyne modified peptides were immobilized, to perform the phenotype characterization of extracellular vesicles (EVs). This strategy represents a convenient method to reduce the number of analysis, thus possible systematic or random errors, besides offering a drastic shortage in time, reagents and costs.


Assuntos
Peptídeos , Polímeros , Alcinos , Azidas , Análise em Microsséries , Propriedades de Superfície
8.
Anal Chim Acta ; 1187: 339162, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34753576

RESUMO

In this work, an auto-identify sensor was constructed for rapid and high-precision detection of L-histidine. The proposed strategy is based on the auto-identify algorithm and the aggregation of alkynyl and azide functionalized gold nanoparticles induced by the Cu+ catalyzed azides and alkynes cycloaddition (CuAAC) reaction. Specially, the color of scattering light spots for the aggregated gold nanoparticle (AuNPs) caused by CuAAC reaction was quite different from that of the monomers. However, L-histidine can bind to Cu2+ and inhibits the production of Cu+, hence preventing the aggregation of AuNPs. Therefore, there is a distinct change of color as the addition of L-histidine under dark-field microscopy. Then, L-histidine can be quantitatively detected by combining the color change with the Meanshift algorithm accurately and automatically. Such proposed method has been successfully applied for the detection of L-histidine in serum sample with satisfying result.


Assuntos
Ouro , Nanopartículas Metálicas , Algoritmos , Alcinos , Azidas , Catálise , Química Click , Cobre , Reação de Cicloadição , Histidina
9.
BMC Infect Dis ; 21(1): 1154, 2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34774018

RESUMO

BACKGROUND: In 2019, the World Health Organisation (WHO) recommended Dolutegravir (DTG) as the preferred first-line antiretroviral treatment (ART) for all persons with HIV. ART regimen switches may affect HIV treatment adherence. We sought to describe patient experiences switching from EFV to DTG-based ART in Kampala, Uganda. METHODS: Between July and September 2019, we purposively sampled adults living with HIV who had switched to DTG at the Infectious Diseases Institute HIV clinic. We conducted in-depth interviews with adults who switched to DTG, to explore their preparation to switch and experiences on DTG. Interviews were audio-recorded, transcribed and analysed thematically using Atlas ti version 8 software. RESULTS: We interviewed 25 adults: 18 (72%) were women, and the median age was 35 years (interquartile range [IQR] 30-40). Median length on ART before switching to DTG was 67 months (IQR 51-125). Duration on DTG after switching was 16 months (IQR 10-18). Participants reported accepting provider recommendations to switch to DTG mainly because they anticipated that swallowing a smaller pill once a day would be more convenient. While most participants initially felt uncertain about drug switching, their providers offer of frequent appointments and a toll-free number to call in the event of side effects allayed their anxiety. At the same time, participants said they felt rushed to switch to the new ART regimen considering that they had been on their previous regimen(s) for several years and the switch to DTG happened during a routine visit when they had expected their regular prescription. Some participants felt unprepared for new adverse events associated with DTG and for the abrupt change in treatment schedule. Most participants said they needed additional support from their health providers before and after switching to DTG. CONCLUSION AND RECOMMENDATIONS: Adults living with HIV stable on an EFV-based regimen but were switched to DTG in a program-wide policy change found the duration between counselling and drug switching inadequate. DTG was nonetheless largely preferred because of the small pill size, once daily dosing, and absence of EFV-like side effects. Community-engaged research is needed to devise acceptable ways to prepare participants for switching ART at scale.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adulto , Alcinos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Ciclopropanos , Feminino , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Oxazinas , Avaliação de Resultados da Assistência ao Paciente , Piperazinas , Piridonas , Uganda
10.
Chemistry ; 27(65): 16093-16097, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34633713

RESUMO

Sydnones are highly stable mesoionic 1,3-dipoles that react with cyclooctynes through strain-promoted sydnone-alkyne cycloaddition (SPSAC). Although sydnones have been shown to be valuable bioorthogonal chemical reporters for the labeling of proteins and complex glycans, nucleic acids have not yet been tagged by SPSAC. Evaluation of SPSAC kinetics with model substrates showed fast reactions with cyclooctyne probes (up to k=0.59 M-1 s-1 ), and two different sydnones were effectively incorporated into both 2'-deoxyuridines at position 5, and 7-deaza-2'-deoxyadenosines at position 7. These modified nucleosides were synthetically incorporated into single-stranded DNAs, which were successfully postsynthetically labeled with cyclooctyne probes both in vitro and in cells. These results show that sydnones are versatile bioorthogonal tags and have the premise to become essential tools for tracking DNA and potentially RNA in living cells.


Assuntos
Alcinos , Sidnonas , Reação de Cicloadição , DNA , Proteínas
11.
J Phys Chem B ; 125(42): 11717-11731, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34644090

RESUMO

Rod-shaped oligo(p-phenyleneethynylene) (OPE) offers an attractive π-framework for the development of solution-processable highly fluorescent molecules having tunable hybridized local and charge transfer (HLCT) excited states and (reverse) intersystem crossing ((R)ISC) channels. Herein, an HLCT oligo(p-phenyleneethynylene) library was studied for the first time in the literature in detail systematically via experiment and theory. The design, synthesis, and full characterization of a new highly fluorescent (ΦPL-solution ∼ 1) sky blue emissive 4',4‴-((2,5-bis((2-ethylhexyl)oxy)-1,4-phenylene)bis(ethyne-2,1-diyl))bis(N,N-diphenyl-[1,1'-biphenyl]-4-amine) (2EHO-TPA-PE) was also reported. The new molecule consists of a D'-Ar-π-D-π-Ar-D' molecular architecture with an extended π-spacer and no acceptor unit, and detailed structural, physicochemical, single-crystal, and optoelectronic characterizations were performed. A high solid-state quantum efficiency (ΦPL-solid state ∼ 0.8) was achieved as a result of suppressed exciton-phonon/vibronic couplings (no π-π interactions and multiple (14 per dimeric form) strong C-H···π interactions). Strong solution-phase/solid-state dipole-dependent tunable excited state behavior (local excited (LE) → HLCT → charge transfer (CT)) and decay dynamics covering a wide spectral region were demonstrated, and the CT state was observed to be highly fluorescent despite extremely large Stokes shift (∼130 nm)/fwhm (∼125 nm) and significant charge separation (0.75 charge·nm). Employing the Lippert-Mataga model, along with detailed photophysical studies and TDDFT calculations, key relationships between molecular design-electronic structure-exciton characteristics were elucidated with regards to HLCT and hot exciton channel formations. The interstate coupling between CT and LE states and the interplay of this coupling with respect to medium polarity were explored. A key relationship between excited-state symmetry breaking process and the formation of HLCT state was discussed for TPA-ended rod-shaped OPE π-systems. (R)ISC-related delayed fluorescence (τ ∼ 2-6 ns) processes were evident following the prompt decays (∼0.4-0.9 ns) both in the solution and in the solid-state. As a unique observation, the delayed fluorescence could be tuned and facilitated via small dielectric changes in the medium. Our results and the molecular engineering perspectives presented in this study may provide unique insights into the structural and electronic factors governing tunable excited state and hot-exciton channel formations in OPEs for (un)conventional solution-processed luminescence applications.


Assuntos
Luminescência , Alcinos , Éteres , Fluorescência , Estrutura Molecular
12.
Chemistry ; 27(60): 14846-14850, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34611939

RESUMO

Alkyne aminopalladation reactions starting from tosylamides are reported. The emerging vinylic Pd species are converted either in an intramolecular Heck reaction with olefinic units or in an intermolecular Suzuki reaction by using boronic acids exhibiting broad functional group tolerance. Tetra(hetero)substituted tosylated enamines are obtained in a simple one-pot process.


Assuntos
Alcenos , Alcinos , Ácidos Borônicos , Catálise , Estrutura Molecular , Paládio
13.
Nutrients ; 13(10)2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34684572

RESUMO

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.


Assuntos
Alcinos/sangue , Alcinos/uso terapêutico , Benzoxazinas/sangue , Benzoxazinas/uso terapêutico , Ciclopropanos/sangue , Ciclopropanos/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Vitamina D/farmacologia , Vitaminas/farmacologia , Adulto , Estudos de Coortes , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Estações do Ano , Resultado do Tratamento , Vitamina D/sangue , Vitaminas/sangue
14.
IET Nanobiotechnol ; 15(7): 627-637, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34695297

RESUMO

Infection with human immunodeficiency virus (HIV)-1 causes immunological disorders and death worldwide which needs to be further assisted by novel anti-retroviral drug delivery systems. Consequently, finding newer anti-retroviral pharmaceuticals by using biocompatible, biodegradable nanomaterials comprising a nanoparticle as core and a therapeutic agent is of high global interest. In this experiment, a second generation of a negatively charged nano-biopolymer linear globular G2 dendrimer was carefully conjugated and loaded with well-known anti-HIV drugs lamivudine and efavirenz, respectively. They were characterised by a variety of analytical methods such as Zetasizer, Fourier-transform infrared spectroscopy, elemental analysis and liquid chromatography-mass spectroscopy. Additionally, conjugated lamivudine and loaded efazirenz with globular PEGylated G2 dendrimer were tested on an HEK293 T cell infected by single-cycle replicable HIV-1 virion and evaluated using XTT test and HIV-1 P24 protein load. The results showed that lamivudine-conjugated G2 significantly decreased retroviral activity without any cell toxicity. This effect was more or less observed by efavirenz-loaded G2. These nano-constructs are strongly suggested for further in vivo anti-HIV assays.


Assuntos
Dendrímeros , Lamivudina , Alcinos , Benzoxazinas/farmacologia , Ciclopropanos , Sistemas de Liberação de Medicamentos , Células HEK293 , Humanos , Lamivudina/farmacologia
15.
J Med Microbiol ; 70(10)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34668851

RESUMO

Introduction. Biofilm formation and hemolysis are closely related to the pathogenicity of Staphylococcus aureus.Hypothesis/Gap Statement. Strategies that reduce the mortality of S. aureus infections may involve novel antimicrobials and/or drugs that decrease S. aureus virulence, such as biofilm formation. The antiviral drug efavirenz is a non-nucleoside reverse transcriptase inhibitor, which also has shown antibacterial effect on Bacillus subtilis and Escherichia coli. Its effect on pathogen virulence has not yet been explored.Aim. This study investigates the antimicrobial and anti-virulence effect of efavirenz on S. aureus.Methodology. Biofilm biomasses were detected by crystal violet staining. Hemolysis activities of S. aureus were determined by rabbit erythrocytes lysis assay. RNA levels of transcriptional regulatory genes, biofilm-related genes, and virulence-related genes of S. aureus were determined by RT-qPCR.Results. Efavirenz showed an inhibitory effect on the growth of S. aureus, Enterococcus faecalis and Streptococcus agalactiae at 50 µM. Efavirenz significantly inhibited biofilm formation of both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) at 25 µM, but did not affect the growth of planktonic S. aureus cells. Moreover, hemolysis by S. aureus was inhibited by efavirenz at 25 µM. The expression levels of RNA transcriptional regulatory genes (agrA, agrC, sigB, saeR and saeS), biofilm-related genes (cidA, clfA, clfB, fnbA, fnbB), and virulence-related genes (hla, hld, staphopain B, alpha-3 PSM, beta PSM, delta PSM) of S. aureus decreased significantly at 25 µM efavirenz.Conclusion. Efavirenz inhibits S. aureus biofilm formation and virulence in vitro.


Assuntos
Alcinos/farmacologia , Antibacterianos/farmacologia , Benzoxazinas/farmacologia , Biofilmes/efeitos dos fármacos , Ciclopropanos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Virulência/efeitos dos fármacos
16.
Chemistry ; 27(62): 15545-15553, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34469004

RESUMO

Various triaminocyclopentadienyl ruthenium complexes have been synthesized from Ru3 (CO)12 . The new complexes were tested for their ability to catalyze cascade conversions of propargyl alcohols. Their associated catalytic activities complement the activities of known diaminocyclopentadienone ruthenium complexes. In particular, the substrate scope of catalytic cycloadditions with 3-ketolactones or phloroglucinol derivatives is extended to terpenoid-derived propargyl alcohols containing an internal alkyne moiety. A wide range of cyclic terpenoid and phloroglucinol adducts are obtained by complementary application of both types of catalysts.


Assuntos
Rutênio , Álcoois , Alcinos , Catálise
17.
J Org Chem ; 86(19): 13693-13701, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34529434

RESUMO

A transition-metal-free postmodification of the Groebke-Blackburn-Bienaymé (GBB) reaction for the synthesis of spiro[chromene-imidazo[1,2-a]pyridin]-3'-imine was discovered. The unusual transformation represents the first example of activation and the reaction of the imidazole carbon atom. In this postcondensational modification, KOt-Bu acts as a base, which, after the isomerization of an alkyne moiety to allene, causes the next unique nucleophilic reaction of the imidazole carbon atom that results in spirocyclic structures. The proposed reaction mechanism was confirmed based on the DFT calculations.


Assuntos
Iminas , Elementos de Transição , Alcinos , Benzopiranos , Ciclização
18.
Chemistry ; 27(62): 15392-15395, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34498756

RESUMO

A method for the selective tryptophan modification and labelling of tryptophan-containing peptides is described. Photoirradiation of acylsilanes generates reactive siloxycarbenes which undergo H-N-insertion into the indole moiety of tryptophan to give stable silyl protected hemiaminals. This method is successfully applied to chemically modify various tryptophan containing oligopeptides. The method enables the selective introduction of alkynes to peptides that are eligible for further alkyne-azide click chemistry. In addition, the dansyl fluorophore can be conjugated to a peptide using this approach.


Assuntos
Azidas , Triptofano , Alcinos , Química Click , Oligopeptídeos
19.
AIDS Patient Care STDS ; 35(9): 335-341, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34524919

RESUMO

Integrase inhibitors appear to increase body weight, but paradoxically some data indicate that raltegravir (RAL) may decrease liver fat. Our objective was to study the effects of switching from a protease inhibitor (PI) or efavirenz (EFV) to RAL on liver fat, body composition, and metabolic parameters among people living with HIV (PLWH) with high risk for nonalcoholic fatty liver disease (NAFLD). We randomized overweight PLWH with signs of metabolic syndrome to switch a PI or EFV to RAL (n = 19) or to continue unchanged antiretroviral therapy (control, n = 24) for 24 weeks. Liver fat was measured by magnetic resonance spectroscopy (MRS), body composition by magnetic resonance imaging, and bioimpedance analysis; subcutaneous fat biopsies were obtained. Median (interquartile range) liver fat content was normal in RAL 2.3% (1.1-6.0) and control 3.1% (1.6-7.3) group at baseline. Liver fat and visceral adipose tissue remained unchanged during the study. Body weight [from 85.9 kg (76.1-97.7) to 89.3 (78.7-98.7), p = 0.019], body fat mass [from 20.3 kg (14.6-29.7) to 22.7 (17.0-29.7), p = 0.015], and subcutaneous adipose tissue (SAT) volume [from 3979 mL (2068-6468) to 4043 (2206-6433), p = 0.048] increased, yet, adipocyte size [from 564 pL (437-733) to 478 (423-587), p = 0.019] decreased in RAL but remained unchanged in control group. Circulating lipids and inflammatory markers improved in RAL compared to control group. The median liver fat measured by MRS was unexpectedly within normal range in this relatively small study population with presumably high risk for NAFLD contradicting high prevalence of NAFLD reported with other methods. Despite weight gain, increase in SAT together with decreased adipocyte size and reduced inflammation may reflect improved adipose tissue function. Clinical Trial Registration number: NCT03374358.


Assuntos
Infecções por HIV , Tecido Adiposo , Alcinos , Benzoxazinas , Composição Corporal , Ciclopropanos , Infecções por HIV/tratamento farmacológico , Humanos , Fígado , Inibidores de Proteases , Raltegravir Potássico/uso terapêutico
20.
Chemistry ; 27(65): 16242-16249, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34492156

RESUMO

We report the synthesis of conceptually new prototypes of molecular winches with the ultimate aim to investigate the work performed by a single ruthenium-based molecular motor anchored on a surface by probing its ability to pull a load upon electrically-driven directional rotation. According to a technomimetic design, the motor was embedded in a winch structure, with a long flexible polyethylene glycol chain terminated by an azide hook to connect a variety of molecular loads. The structure of the motor was first derivatized by means of two sequential cross-coupling reactions involving a penta(4-halogenophenyl)cyclopentadienyl hydrotris(indazolyl)borate ruthenium(II) precursor and the resulting benzylamine derivative was next exploited as key intermediate in the divergent synthesis of a family of nanowinch prototypes. A one-pot method involving sequential peptide coupling and Cu-catalyzed azide-alkyne cycloaddition was developed to yield four loaded nanowinches, with load fragments encompassing triptycene, fullerene and porphyrin moieties.


Assuntos
Azidas , Rutênio , Alcinos , Ciclização , Reação de Cicloadição
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