Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 191
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Eur J Med Chem ; 182: 111618, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31434041

RESUMO

The α7 nicotinic acetylcholine receptor (α7 nAChR) has emerged as a promising therapeutic target for schizophrenia. In our previous work, a novel series of α7-nAChR agonists bearing scaffold of indolizine were discovered. To explore the effect of aromaticity on the activity and find more active agents, herein, fused heterocyclic carboxamide derivatives were designed and synthesized in this study. Based on the evaluation by two-electrode voltage clamp in Xenopus oocytes, 27 of the synthesized compounds showed obvious agonism of α7 nAChR. Particularly, compounds 10a and 10e showed significantly higher Emax than EVP-6124. The result illustrated the importance of aromaticity to the activity of agonism. Compound 10a, which showed EC50 of 1.88 µM and Emax of 72.4%, was further characterized comprehensively, including co-application with type II positive allosteric modulator PNU-120596, selectivity with other closely related ligand-gated ion channel, etc. The results showed that 10a showed moderate selectivity over other subtypes such as α4ß2 and α3ß4 nAChR. 10a evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. The analysis of binding mode and understanding of structure-activity relationship provided insights to develop more potent novel α7-nAChR agonists.

2.
J Med Chem ; 62(14): 6645-6664, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31268308

RESUMO

Alzheimer's disease (AD) is one of the most challenging diseases around the world with no effective clinical treatment. Previous studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive therapeutic target for AD. Herein, we report 3-substituted indolin-2-one derivatives as the first isoform-selective JNK3 inhibitors by multistage screening. In this study, comparative structure-based virtual screening was performed, and J30-8 was identified with a half-maximal inhibitory concentration of 40 nM, which exhibited over 2500-fold isoform selectivity and marked kinome-wide selectivity. Further study indicated that 1 µM J30-8 exhibited neuroprotective activity in vitro so as to alleviate the spatial memory impairment in vivo through reducing plaque burden and inhibiting the phosphorylation of JNKs, Aß precursor protein, and Tau protein. All of these indicated J30-8 as proved isoform-selective JNK3 inhibitors that might serve as a useful tool for further JNK3 studies with AD as well as for the development of JNK3 inhibitors for the potential treatment of neurodegenerative diseases.

3.
Nucleic Acids Res ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31361892

RESUMO

Application of viral vectors in gene delivery is attracting widespread attention but is hampered by the absence of control over transduction, which may lead to non-selective transduction with adverse side effects. To overcome some of these limitations, we proposed an unnatural amino acid aided caging-uncaging strategy for controlling the transduction capability of a viral vector. In this proof-of-principle study, we first expanded the genetic code of the lentiviral vector to incorporate an azido-containing unnatural amino acid (Nϵ-2-azidoethyloxycarbonyl-l-lysine, NAEK) site specifically within a lentiviral envelope protein. Screening of the resultant vectors indicated that NAEK incorporation at Y77 and Y116 was capable of inactivating viral transduction upon click conjugation with a photo-cleavable chemical molecule (T1). Exposure of the chimeric viral vector (Y77-T1) to UVA light subsequently removed the photo-caging group and restored the transduction capability of lentiviral vector both in vitro and in vivo. Our results indicate that the use of the photo-uncage activation procedure can reverse deactivated lentiviral vectors and thus enable regulation of viral transduction in a switchable manner. The methods presented here may be a general approach for generating various switchable vectors that respond to different stimulations and adapt to different viral vectors.

4.
Cell Rep ; 27(12): 3684-3695.e4, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216484

RESUMO

cADPR is a well-recognized signaling molecule by modulating the RyRs, but considerable debate exists regarding whether cADPR can bind to and gate the TRPM2 channel, which mediates oxidative stress signaling in diverse physiological and pathological processes. Here, we show that purified cADPR evoked TRPM2 channel currents in both whole-cell and cell-free single-channel recordings and specific binding of cADPR to the purified NUDT9-H domain of TRPM2 by surface plasmon resonance. Furthermore, by combining computational modeling with electrophysiological recordings, we show that the TRPM2 channels carrying point mutations at H1346, T1347, L1379, S1391, E1409, and L1484 possess distinct sensitivity profiles for ADPR and cADPR. These results clearly indicate cADPR is a bona fide activator at the TRPM2 channel and clearly delineate the structural basis for cADPR binding, which not only lead to a better understanding in the gating mechanism of TRPM2 channel but also shed light on a cADPR-induced RyRs-independent Ca2+ signaling mechanism.

5.
iScience ; 15: 452-466, 2019 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-31128467

RESUMO

SARM1, an NAD-utilizing enzyme, regulates axonal degeneration. We show that CZ-48, a cell-permeant mimetic of NMN, activated SARM1 in vitro and in cellulo to cyclize NAD and produce a Ca2+ messenger, cADPR, with similar efficiency as NMN. Knockout of NMN-adenylyltransferase elevated cellular NMN and activated SARM1 to produce cADPR, confirming NMN was its endogenous activator. Determinants for the activating effects and cell permeability of CZ-48 were identified. CZ-48 activated SARM1 via a conformational change of the auto-inhibitory domain and dimerization of its catalytic domain. SARM1 catalysis was similar to CD38, despite having no sequence similarity. Both catalyzed similar set of reactions, but SARM1 had much higher NAD-cyclizing activity, making it more efficient in elevating cADPR. CZ-48 acted selectively, activating SARM1 but inhibiting CD38. In SARM1-overexpressing cells, CZ-48 elevated cADPR, depleted NAD and ATP, and induced non-apoptotic death. CZ-48 is a specific modulator of SARM1 functions in cells.

6.
Chembiochem ; 2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31081167

RESUMO

CD38 is a multi-functional signaling enzyme that catalyzes the biosynthesis of two calcium-mobilizing second messengers: cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate. It also regulates intracellular nicotinamide adenine dinucleotide (NAD) contents, associated with multiple pathophysiological processes such as aging and cancer. As such, enzymatic inhibitors of CD38 offer great potential in drug development. Here, through virtual screening and enzymatic assays, we discovered compound LX-102, which targets CD38 on the side opposite its enzymatic pocket with a binding affinity of 7.7 µm. It inhibits the NADase activity of CD38 with an IC50 of 14.9 µm. Surface plasmon resonance (SPR) and hydrogen/deuterium exchange and mass spectrometry experiments verified that LX-102 competitively binds to the epitope of the therapeutic SAR 650984 antibody in an allosteric manner. Molecular dynamics simulation was performed to demonstrate the binding dynamics of CD38 with the allosteric ligand. In summary, we established that the cavity to which SAR 650984 binds was an allosteric site and was accessible for the rational design of small chemical modulators of CD38. The lead compound LX-102 that we identified in this study could also be a useful tool for probing CD38 functions and promoting drug discovery.

7.
Sci Rep ; 9(1): 4311, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30867535

RESUMO

The aim of this study was to determine the effects of sodium selenate (15, 30, 45, 60, 75, 90, and 105 mg kg-1) on the germination and seedling growth of Changnongjing 1 rice (Oryza sativa L.) at 25 °C and 30 °C. Low selenate concentrations induced shorter and more uniform germination periods than did ultrapure water at both temperatures. Seedlings primed with low selenate concentrations were superior to those primed with ultrapure water in terms of plant height, fresh weight, dry matter accumulation, and soluble carbohydrate and protein contents. Lower selenate concentrations (15-75 mg kg-1) induced higher chlorophyll and phenol contents in seedlings than did ultrapure water. Lower selenate concentrations also increased the superoxide dismutase (SOD), peroxidase (POX), catalase (CAT), and glutathione peroxidase (GPx) contents in seedlings and significantly decreased the stress-related malondialdehyde (MDA) content compared to ultrapure water. In conclusion, rice seedling germination and growth were promoted by priming with low selenate concentrations (15-75 mg kg-1) but inhibited by priming with high selenate concentrations (90-105 mg kg-1).

8.
Eur J Med Chem ; 171: 221-234, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30925338

RESUMO

Glycogen synthase kinase 3α (GSK-3α) plays a constitutive role in various physiological processes and has been proved to be a therapeutic target for acute myeloid leukemia (AML). In this paper, by means of computer-aided drug design, we discovered a novel chemical series of GSK-3α inhibitors with an IC50 value of 0.033-2.804 µM. The preliminary structure-activity relationship was concluded and, notably, the most potent and isoform-selective compound G28_14 was identified with IC50 values of 33 nM and 218 nM against GSK-3α and -3ß, respectively, exhibiting a nearly ten-fold isoform-selectivity. Further cell viability assays and colony formation assays revealed that G28_14 suppressed cell survival by impairing cell proliferation by up to 90% in two AML cell lines. Moreover, surface marker expression analysis demonstrated that G28_14 induced terminal differentiation with a high level of CD11b, CD11c, and CD14. Western immunoblotting showed that G28_14 isoform-selectively inhibited the phosphorylation of GSK-3α in-cell without activating Wnt/ß-catenin signaling. In addition, to elucidate its structure-activity relationship, the binding mode of this chemical series was proposed using molecular docking and molecular dynamics simulations. Taken together, this chemical series is worth developing as differentiation therapies for the treatment of AML.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 166: 328-338, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30731401

RESUMO

Glycyrrhetinic acid (GA) is a major constituent of the herb Glycyrrhiza glabra, and many of its derivatives demonstrate a broad spectrum of antiviral activities. In the current study, 18 water-soluble ß-cyclodextrin (CD)-GA conjugates, in which GA was covalently coupled to the primary face of ß-CD using 1,2,3-triazole moiety along with varying lengths of linker, were synthesized via copper-catalyzed azide-alkyl cycloaddition reaction. Benefited from the attached ß-CD moiety, all these conjugates showed lower hydrophobicity (AlogP) compared with their parent compound GA. With the exception of per-O-methylated ß-CD-GA conjugate (35), all other conjugates showed no significant cytotoxicity to MDCK cells, and these conjugates were then screened against A/WSN/33 (H1N1) virus using the cytopathic effect assay. The preliminary results indicated that six conjugates showed promising antiviral activity, and the C-3 and C-30 of GA could tolerate some modifications. Our findings suggested that GA could be used as a lead compound for the development of potential anti-influenza virus agents.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Água/química , beta-Ciclodextrinas/química , Animais , Antivirais/química , Técnicas de Química Sintética , Cães , Ácido Glicirretínico/química , Células Madin Darby de Rim Canino , Solubilidade , Relação Estrutura-Atividade
10.
Appl Microbiol Biotechnol ; 103(5): 2181-2192, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30656392

RESUMO

Itaconic acid, a promising platform chemical, has been applied in many fields of industrial production. As a potential candidate for itaconic acid production, Yarrowia lipolytica possesses several innate abilities such as the tolerance of low-pH and high-shear stress, fast growth rate, cultivation flexibility, and easy for genetic manipulation. Here, Y. lipolytica Po1f which was tested to show high tolerance to itaconic acid could accumulate itaconic acid (0.363 g/L) by expressing the Aspergillus terreus cis-aconitic acid decarboxylase (CAD). Then, we tried to improve the supply and transport of the immediate precursor cis-aconitic acid by overexpressing a series of genes; these results indicate that overexpression of mitochondrial cis-aconitate transporter MTT is beneficial to the itaconic acid biosynthesis in Y. lipolytica. Further culture optimization enabled 22.03 g/L of itaconic acid to be produced in bioreactors, about 60-fold improvement over the initial titer, which is the highest itaconic acid production achieved at low pH by yeast reported worldwide, to data. This study demonstrates the great potential of Y. lipolytica as an industrial platform for itaconic acid production.


Assuntos
Reatores Biológicos/microbiologia , Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias/metabolismo , Succinatos/metabolismo , Yarrowia/genética , Yarrowia/metabolismo , Ácido Aconítico/metabolismo , Aspergillus/genética , Carboxiliases/genética , Fermentação , Proteínas de Membrana Transportadoras/genética
11.
Biomaterials ; 197: 182-193, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30660994

RESUMO

Antisense oligonucleotides (ASOs) usually contain a fully phosphorothioate (PS) backbone, which possibly interact with many genes and proteins under intracellular conditions. G3139 is an ASO that targets Bcl-2 mRNA and induces cell apoptosis. Here, we report a kind of cytidinyl-lipid combined with a cationic lipid (DNCA/CLD, molar ration, 28:3, named mix), which may interact with oligonucleotides via H-bond formation, pi-stacking and electrostatic interaction, accompanied by low zeta potentials. The IC50 value of G3139 delivered by mix-lipid reduced from above 20 µM to 0.158 µM for MCF-7/ADR, and exhibited stronger antiproliferation upon other cancer cell lines. In addition, PS modification in the 3'-half of G3139 (especially at positions 13-16) enhanced serum stability, target specificity and anticancer activity. Also, a locked nucleic acid (LNA) gapmer G3139 (LNA-G3139) showed superior antiproliferation (78.5%) and Bcl-2 mRNA suppression effects (85.5%) at 200 nM, mainly due to its high complementary RNA affinity. More apoptosis-associated targets were identified, and a lower level of non-specific protein binding (HSA) revealed that both antisense and aptamer mechanisms might simultaneously exist. A combination of a new delivery system and chemical modifications, such as in LNA-G3139, may have potential clinical application prospects in the future.

12.
Eur J Med Chem ; 163: 560-568, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30554131

RESUMO

It is urgently necessary to develop more effective anti-influenza agents due to the continuous emergence of drug-resistant strains of influenza virus. Our earlier studies have identified that certain pentacyclic triterpene derivatives are effective inhibitors of influenza virus infection. In the present study, a series of C-28 modified pentacyclic triterpene derivatives via conjugation with a series of polyphenols were synthesized, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in MDCK (Madin-Darby canine kidney) cells were evaluated. Four compounds 23m, 23o, 23q and 23s displayed robust anti-influenza potency with averaged IC50 values at the low-micromole level, surpassing the potency of oseltamivir. In addition, the in vitro cytotoxic activity of the four conjugates against MDCK cells showed no toxicity at 100 µM. Further mechanism studies of compound 23s, one of the best representative conjugates with IC50 value of 5.80 µM and a selective index (SI) value of over 17.2, by hemagglutination inhibition (HI), surface plasmon resonance and molecular modeling indicated that this conjugate bound tightly to the viral envelope hemagglutinin (KD = 15.6 µM), thus blocking the invasion of influenza viruses into host cells.


Assuntos
Antivirais/síntese química , Triterpenos Pentacíclicos/farmacologia , Polifenóis/química , Animais , Antivirais/farmacologia , Cães , Hemaglutinação/efeitos dos fármacos , Humanos , Vírus da Influenza A Subtipo H1N1 , Concentração Inibidora 50 , Células Madin Darby de Rim Canino , Modelos Moleculares , Infecções por Orthomyxoviridae/tratamento farmacológico , Triterpenos Pentacíclicos/síntese química , Relação Estrutura-Atividade , Internalização do Vírus/efeitos dos fármacos
13.
Methods Mol Biol ; 1870: 151-163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30539553

RESUMO

Based on the nucleobase rich character of the binding pocket of A-site 16S ribosomal RNA of Escherichia coli, it was proposed that the neamine moiety of synthesized Neamine-nucleoside conjugates could bind to the groove of RNA while the nucleobase moiety would bind specifically to the sequence of the 16S rRNA A-site fragment. Thus the designed conjugate compound 5 was found to have the same dissociation constant as neamine for binding to 16S rRNA and the neamine-amino acid substituted nucleoside conjugate 8 and 9 showed 6.3 and 4.8 times greater RNA binding affinity, respectively, as compared with neamine. The results obtained successfully demonstrate the need for chemically modifying neamine and probe the changes induced using NMR protocols to assist in the discovery of new aminoglycoside antibiotics.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Framicetina/farmacologia , Nucleosídeos/farmacologia , RNA Bacteriano , RNA Ribossômico 16S , Framicetina/química , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/química
14.
Microbiologyopen ; : e760, 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30421866

RESUMO

The Asian citrus psyllid, Diaphorina citri Kuwayama, is the most serious pest of citrus worldwide. It acts as a vector for a group of phloem-limited bacteria (Candidatus Liberibacter spp.) that causes Huanglongbing (HLB) disease. Thus, D. citri management is an important strategy against HLB, and biological control is currently considered as the most effective method because of the unsustainable and negative side effects of chemical control. Here, we isolated a new strain of entomopathogenic fungus, Cordyceps javanica (GZQ-1), from one cadaver of D. citri adult based on its morphological and phylogenetic data. Five conidial concentrations of the C. javanica pathogen (1 × 103 , 1 × 104 , 1 × 105 , 1 × 106 , and 1 × 107 conidia/ml) were assessed against six life stages of D. citri (1st-5th instar nymphs and adults). Results showed that C. javanica GZQ-1 was highly pathogenic to D. citri nymphs (69.49%-90.87% mortality) and adults (69.98% mortality). The LC50 and LT50 values of C. javanica against 1st-2nd instar (younger), 3rd-4th instar (middle aged), 5th instar (older), and adults were 1.20 × 105 , 1.10 × 106 , 4.47 × 106 , 8.12 × 106 conidia/ml and 4.25, 4.51, 5.17, 5.49 days, respectively. Moreover, glasshouse experiments indicated that this C. javanica GZQ-1 caused higher infection rates of D. citri adults compared to two other fungal strains we previously isolated in the laboratory, Cordyceps fumosorosea (IF010) and Metarhizium anisopliae (CNGD7).

15.
Sci Adv ; 4(11): eaau8408, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30474060

RESUMO

A trimer-of-hairpins motif has been identified in triggering virus-cell fusion within a variety of viral envelopes. Chemically manipulating such a motif represents current repertoire of viral fusion inhibitors. Here, we report that triterpenoids, a class of natural products, antagonize this trimer-of-hairpins via its constitutive heptad repeat-2 (HR2), a prevalent α-helical coil in class I viral fusion proteins. Triterpenoids inhibit the entry of Ebola, Marburg, HIV, and influenza A viruses with distinct structure-activity relationships. Specifically, triterpenoid probes capture the viral envelope via photocrosslinking HR2. Profiling the Ebola HR2-triterpenoid interactions using amino acid substitution, surface plasmon resonance, and nuclear magnetic resonance revealed six residues accessible to triterpenoids, leading to wrapping of the hydrophobic helix and blocking of the HR1-HR2 interaction critical in the trimer-of-hairpins formation. This finding was also observed in the envelopes of HIV and influenza A viruses and might potentially extend to a broader variety of viruses, providing a mechanistic insight into triterpenoid-mediated modulation of viral fusion.

16.
J Org Chem ; 83(21): 13166-13177, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30354127

RESUMO

Benefiting from their unique properties, the development of structurally novel and easily accessible medium rings is of significant interest in the pharmaceutical industry and academic research. However, synthetic access to medium-ring scaffolds is very difficult due to their rigid skeleton and large-angle strains. In this paper, a new class of medium rings bearing bitriazolyls (MRBTs) was designed, synthesized, identified as a promising new skeleton ligand for the Cu(I)-catalyzed click reaction, and used in site-special modification of protein. One of the MRBTs, 3aa, exhibited a turnover number (TON) as high as 55 000 and dramatic accelerating effects ( kobs = 1.95 M-1 s-1) and ranked among the most efficient ligands for copper-catalyzed alkyne and azide cycloaddition. Unlike the difficult access to other known medium rings, these 7-12-membered MRBTs can be prepared in straightforward, one-step manner from structurally diverse linear terminal diynes and azides. The unique accessibility and intriguing properties therefore imply their broad application perspectives.

17.
Org Biomol Chem ; 16(40): 7488-7497, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30272759

RESUMO

The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was reported to participate in the development of a variety of tumors. BC15 is a DNA aptamer targeting hnRNP A1. Firstly, through sequence truncation, we identified 31-mer sequence BC15-31 as the core sequence of BC15 with a strong binding affinity and high selectivity to the hnRNP A1 protein. Isothymidine (isoT) modification was then applied for the structural optimization of BC15-31, systematic modification and biological evaluation were carried out. Incorporation of isoT in the 1,3 sites at the 5'-end of BC15-31 can significantly enhance the protein affinity. Chemical modifications close to the 3'-end can greatly improve the stability of the aptamer. Furthermore, BC15-31 modified with isoT at both the 5'-end and 3'-end displayed an additive effect with enhanced bioactivity and stability at the same time. Our study strategy on BC15 provides a useful guideline for chemical modification and optimization of the aptamer for further clinical application.

18.
Org Biomol Chem ; 16(38): 7029-7035, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30234864

RESUMO

Manually controlling siRNA activity is an essentially important way to spatiotemporally investigate gene expression and function. Owing to ease of operation and precise manipulation, light can be used for controlled regulation of siRNA-induced gene silencing. Here, we developed a series of caged siRNAs with folic acid modification at the 5' terminus of the antisense strand of the siRNA through a photolabile linker. The attachment of the folic acid moiety temporarily masked the corresponding siRNA activity. Upon illumination, these caged siRNAs were activated, and their gene silencing activities were restored. Based on this strategy, we successfully photomodulated gene expression of both an exogenous gene (for green fluorescent protein, GFP) and an endogenous gene (for mototic kinesin-5, Eg5) in cells.

19.
J Pharmacol Exp Ther ; 367(1): 147-154, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30076263

RESUMO

Myeloperoxidase (MPO) is a leukocyte-derived redox enzyme that has been linked to oxidative stress and damage in many inflammatory states, including cardiovascular disease. We have discovered aminopyridines that are potent mechanism-based inhibitors of MPO, with significant selectivity over the closely related thyroid peroxidase. 1-((6-Aminopyridin-3-yl)methyl)-3-(4-bromophenyl)urea (Aminopyridine 2) inhibited MPO in human plasma and blocked MPO-dependent vasomotor dysfunction ex vivo in rat aortic rings. Aminopyridine 2 also showed high oral bioavailability and inhibited MPO activity in vivo in a mouse model of peritonitis. Aminopyridine 2 could effectively be administered as a food admixture, making it an important tool for assessing the relative importance of MPO in preclinical models of chronic inflammatory disease.

20.
Biomaterials ; 178: 147-157, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29933101

RESUMO

Lipid derivatives of nucleoside analogs have been highlighted for their potential for effective gene delivery. A novel class of nucleobase-lipids are rationally designed and readily synthesized, comprising thymine/cytosine, an ester/amide linker and an oleyl lipid. The diversity of four nucleobase-lipids termed DXBAs (DOTA, DNTA, DOCA and DNCA) is investigated. Besides, DNCA is demonstrated to be an effective neutral transfection material for nucleic acid delivery, which enbles to bind to oligonucleotides via H-bonding and π-π stacking with reduced toxicity in vitro and in vivo. Several kinds of nucleic acid drugs including aptamer, ssRNA, antisense oligonucleotide, and plasmid DNAs can be delivered by DXBAs, especially DNCA. In particular, G4-aptamer AS1411 encapsulated by DNCA exhibits cellular uptake enhancement, lysosome degradation reduction, cell apoptosis promotion, cell cycle phase alteration in vitro and duration prolongation in vivo, resulting in significant anti-proliferative activity. Our results demonstrate that DNCA is a promising transfection agent for G4-aptamers and exhibites bright application prospects in the permeation improvement of single-stranded oligonucleotides or plasmid DNAs.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA