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1.
Chem Commun (Camb) ; 56(20): 3047-3049, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32048688

RESUMO

A series of aminocarboxylic acid analogues of aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) were chemoenzymatically synthesized via the addition of various mono- and diamine substrates to fumaric acid catalyzed by the enzyme EDDS lyase. Many of these novel AMA and EDDS analogues demonstrate potent inhibition of the bacterial metallo-ß-lactamase NDM-1. Isothermal titration calorimetry assays revealed a strong correlation between the inhibitory potency of the compounds and their ability to bind zinc. Compounds 1a (AMA), 1b (AMB), 5 (EDDS), followed by 1d and 8a, demonstrate the highest synergy with meropenem resensitizing an NDM-1 producing strain of E. coli to this important carbapenem of last resort.


Assuntos
Ácido Aspártico/análogos & derivados , Complexos de Coordenação/farmacologia , Proteínas de Escherichia coli/antagonistas & inibidores , Etilenodiaminas/farmacologia , Succinatos/farmacologia , Zinco/farmacologia , Inibidores de beta-Lactamases/farmacologia , Aminoácidos/química , Aminoácidos/farmacologia , Ácido Aspártico/química , Ácido Aspártico/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Proteínas de Escherichia coli/metabolismo , Etilenodiaminas/química , Estrutura Molecular , Relação Estrutura-Atividade , Succinatos/química , Zinco/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química , beta-Lactamases/metabolismo
2.
J Enzyme Inhib Med Chem ; 35(1): 489-497, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31914827

RESUMO

A series of amino acid-sulphonamide conjugates was prepared through benzotriazole mediated coupling reactions and characterised by 1H-NMR, 13C-NMR, MS, and FTIR spectroscopic techniques as well as elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA VA, and hCA XII. Most of the synthesised compounds showed effective in vitro CA inhibitory properties. The new amino acid-sulphonamide conjugates showed potent inhibitory activity against hCA II, some of them at subnanomolar levels, exhibiting more effective inhibitory activity compared to the standard drug acetazolamide. Some of these sulphonamides were also found to be effective inhibitors of hCA I, hCA VA, and hCA XII, with activity from the low to high nanomolar range.


Assuntos
Aminoácidos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Sulfonamidas/farmacologia , Aminoácidos/síntese química , Aminoácidos/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Sulfonamidas/síntese química , Sulfonamidas/química
3.
Eur J Med Chem ; 186: 111901, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771826

RESUMO

Development of novel antimicrobial agents combating drug resistance is in an urgent need. Herein we report the design and synthesis of a series of short lipo-α/sulfono-γ-AA hybrid peptides. Several short peptides exhibit potent and broad-spectrum antimicrobial activity toward both Gram-positive and Gram-negative bacteria. Membrane depolarization and fluorescence microscopy studies indicate that these short lipo-α/sulfono-γ-AA hybrid peptides can mimic the mechanisms of HDPs to kill bacteria by disrupting bacterial membranes. In addition, these short peptides also show capability to eradicate the biofilm formation of E. coli even at very low concentration. The further development of lipidated α/sulofono-γ-AA hybrid peptides may lead to a new class of antibiotic agents to combat drug resistance.


Assuntos
Aminoácidos/farmacologia , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Peptídeos/farmacologia , Peptidomiméticos/farmacologia , Aminoácidos/síntese química , Aminoácidos/química , Antibacterianos/síntese química , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Peptidomiméticos/síntese química , Peptidomiméticos/química , Relação Estrutura-Atividade
4.
Chem Asian J ; 15(1): 51-55, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31686429

RESUMO

Monocyclic ß-lactams revive the research field on antibiotics, which are threatened by the emergence of resistant bacteria. A six-step synthetic route was developed, providing easy access to new 3-amino-1-carboxymethyl-4-phenyl-ß-lactams, of which the penicillin-binding protein (PBP) inhibitory potency was demonstrated biochemically.


Assuntos
Aminoácidos/farmacologia , Antibacterianos/farmacologia , Dipeptídeos/farmacologia , Iminas/farmacologia , Lactamas/farmacologia , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Aminoácidos/química , Antibacterianos/síntese química , Antibacterianos/química , Dipeptídeos/síntese química , Dipeptídeos/química , Iminas/química , Lactamas/síntese química , Lactamas/química , Estrutura Molecular , Proteínas de Ligação às Penicilinas/metabolismo
5.
Eur J Med Chem ; 185: 111844, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706640

RESUMO

Lung cancer is one of the most malignant tumors with the highest morbidity and mortality. Most of them are non-small cell lung cancer (NSCLC). KRASG12C gene mutation is an important driving factor for NSCLC. However, the development of high-affinity inhibitors targeting KRASG12C mutants remains a daunting challenge. Here, we report the design and development of a series of hydrocarbon-stapled peptides containing d-amino acids to mimic the alpha helix of SOS1. D-hydrocarbon-stapled peptides maintain good alpha helix structure and bind to KRASG12C with high affinity. Subsequent anti-proliferation experiments indicated that D-hydrocarbon-stapled peptide 5 inhibited the proliferation of NSCLC H358 cells carrying KRASG12C. However, it showed no significant anti-proliferative effect on KRASG12S-positive A549 cells, suggesting that peptide 5 selectively inhibits KRASG12C-driven tumor cells. D-hydrocarbon-stapled peptide 5 could also cause the cell cycle of H358 cells to arrest in the G2/M phase and induce apoptosis. No significant cell arrest and apoptosis were observed in A549 cells treated by peptide 5. In summary, the introduction of d-amino acids could improve the affinity and cell selectivity of hydrocarbon peptides. We hope that peptides containing D-form amino acids can provide strategies for further optimization of the KRASG12C/SOS1 inhibitor.


Assuntos
Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Peptídeos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteína SOS1/antagonistas & inibidores , Células A549 , Aminoácidos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína SOS1/metabolismo , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 185: 111839, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708185

RESUMO

The ligustrazine - betulin derivative (TB), TB amino acids derivatives (TB-01 - TB-09) and TB dipeptide derivatives (TB-10 - TB-18) were designed and synthesized. And their in vitro cytotoxic activities were evaluated against four cancer cell lines (Hela, HepG2, BGC-823 and HT-29) and normal cells MDCK by standard methylthiazol tetrazolium (MTT) assay. Most of them demonstrated better antitumor activity than the relevant material betulin. Among them, compound TB-01 showed the best anti-tumor effect on the cancer cells and the lowest toxicity on the normal cells. For example, the cytotoxicity of TB-01 against the cancer cells (mean IC50 = 4.86 ±â€¯1.16 µM) was 3-fold higher than that against the normal cells MDCK (IC50 = 16.11 ±â€¯2.29 µM). Moreover, TB-01 showed better cytotoxic than positive drug cisplatin (DDP) on tumor cells. Besides, the Zebrafish toxicity evaluation test showed that TB-01 demonstrated high biosafety. Subsequently, fluorescent staining, apoptosis detection and cell cycle analysis indicated that TB-01 induced early apoptosis in HepG2 cells and blocked the cell cycle in the G1 phase. In addition, the structure-activity relationships of these derivatives were briefly discussed.


Assuntos
Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Dipeptídeos/farmacologia , Desenho de Drogas , Pirazinas/farmacologia , Triterpenos/farmacologia , Aminoácidos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dipeptídeos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Estrutura Molecular , Pirazinas/química , Relação Estrutura-Atividade , Triterpenos/química , Peixe-Zebra
8.
J Enzyme Inhib Med Chem ; 34(1): 1652-1659, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530034

RESUMO

Eight genetically distinct carbonic anhydrase (EC 4.2.1.1) enzyme families (α-, ß-, γ- δ-, ζ-, η-, θ- and ι-CAs) were described to date. On the other hand, 16 mammalian α-CA isoforms are known to be involved in many diseases such as glaucoma, edema, epilepsy, obesity, hypoxic tumors, neuropathic pain, arthritis, neurodegeneration, etc. Although CA inhibitors were investigated for the management of a variety of such disorders, the activators just started to be investigated in detail for their in vivo effects. This review summarizes the activation profiles of α-, ß, γ-, δ-, ζ- and η- CAs from various organisms (animals, fungi, protozoan, bacteria and archaea) with the most investigated classes of activators, the amines and the amino acids.


Assuntos
Aminas/farmacologia , Aminoácidos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Aminas/síntese química , Aminas/química , Aminoácidos/síntese química , Aminoácidos/química , Bactérias/enzimologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Entamoeba histolytica/enzimologia , Fungos/enzimologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular
9.
Eur J Med Chem ; 182: 111632, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31499363

RESUMO

ß-amino acids and their analogues are gathering increased attention not only because of their antibacterial and antifungal activity, but also for their use in designing peptidomimetics with increased oral bioavailability and resistance to metabolic degradation. In this study, a series of α-phenyl substituted chalcones, α-phenyl, ß-amino substituted dihydrochalcones and ß-amino acid derivatives were synthesized and evaluated for their antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all synthesized derivatives, 10c showed promising antileishmanial efficacy against both extracellular promastigote and intracellular amastigote (IC50 8.2 µM and 20.5 µM respectively) of L. donovani with negligible cytotoxic effect towards J774 macrophages and Vero cells. 10c effectively reduced spleen and liver parasite burden (>90%) in both hamster and Balb/c model of VL without any hepatotoxicity. In vitro pharmacokinetic analysis showed that 10c was stable in gastric fluid and plasma of Balb/c mice at 10 µg/ml. Further analysis of the molecular mechanism revealed that 10c entered into the parasite by depolarizing the plasma membrane rather than forming nonspecific pores and induced molecular events like loss in mitochondrial membrane potential with a gradual decline in ATP production. This, in turn, did not induce programmed cell death of the parasite; rather 10c induced bioenergetic collapse of the parasite by decreasing ATP synthesis through specific inhibition of mitochondrial complex III activity. Altogether, our results allude to the therapeutic potential of ß-amino acid derivatives as novel antileishmanials, identifying them as lead compounds for further exploration in the design of potent candidates for the treatment of visceral leishmaniasis.


Assuntos
Aminoácidos/farmacologia , Antiprotozoários/farmacologia , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Aminoácidos/química , Animais , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Relação Dose-Resposta a Droga , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Leishmania donovani/metabolismo , Leishmaniose Visceral/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Células Vero
10.
Eur J Med Chem ; 182: 111645, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494472

RESUMO

As our research focus on anticancer drugs, two series of novel derivatives of Flexicaulin A (FA), an ent-kaurene diterpene, condensation with amino acid trifluoroacetate were synthesized, and their anti-proliferative activity against four human cancer cell lines (TE-1, MCF-7, A549 and MGC-803) were evaluated. Compared with FA, the anticancer activity and solubility of most derivatives were significantly improved. Among them, compound 6d had the best activity, and its IC50 value against Esophageal cancer cells (TE-1) was up to 0.75 µM. Subsequent cellular mechanism studies showed that compound 6d could inhibit the proliferation of cancer cells, the formation of cell colonies, and increase the level of ROS on TE-1 cells. In addition, 6d could up-regulate the expressions of SAPK/JNK pathway-associated proteins (p-ASK1, p-MKK4 and p-JNK) and pro-apoptotic proteins (Bak, Bad and Noxa), remarkably increase the ratio of Bax to Bcl-2 and activate Cleaved Caspase-3/9/PARP. These results indicate that compound 6d induces apoptosis through the ROS/JNK/Bcl-2 pathway and holds promising potential as an anti-proliferative agent.


Assuntos
Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Ácido Trifluoracético/farmacologia , Aminoácidos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Ácido Trifluoracético/química , Células Tumorais Cultivadas
11.
J Agric Food Chem ; 67(36): 10245-10255, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31389238

RESUMO

Ginseng has been widely used as a functional food in the world because of its well-defined health benefits. Previous studies have confirmed that AD-1, a new ginsenoside derived from ginseng, can ameliorate thioacetamide-induced liver injury and fibrosis in mice. Simultaneously, amino acid supplementation is getting more attention as an important adjuvant therapy in the improvement of hepatopathy. The aim of this study was to conjugate AD-1 with several selected amino acids and investigate the cytotoxicity of the obtained conjugates in activated t-HSC/Cl-6 cells and normal human liver cells (LO2). Structure-activity relationships of conjugates and underlying mechanisms of the effect are also explored. The results indicated that conjugate 7c remarkably inhibited cell proliferation in activated t-HSC/Cl-6 cells (IC50 = 3.8 ± 0.4 µM) and appeared to be nontoxic to LO2. Besides, conjugate 7c had a relatively good plasma stability. Further study demonstrated that inducing S-phase arrest and activation of mitochondrial-mediated apoptosis were included in the mechanisms underlying the efficiency of conjugate 7c. These findings provided further insight into designing functional foods (ginsenoside and amino acid) for the application in prevention or improvement of liver fibrosis.


Assuntos
Aminoácidos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ginsenosídeos/farmacologia , Células Estreladas do Fígado/citologia , Aminoácidos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ginsenosídeos/química , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos
12.
Mar Drugs ; 17(8)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416181

RESUMO

The objective of this research was to extract and prepare mycosporine-like amino acids (MAAs) and investigate the mechanism by which they act against UV-induced skin photoaging in Institute of Cancer Research (ICR ) mice. MAAs such as porphyra-334 and shinorine were extracted from Porphyra yezoensis, separated, and purified using column chromatography with SA-2 cation exchange resin. The effects of MAAs on the activity of endogenous antioxidant enzymes, namely total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA) were analyzed in mouse skin tissue. Pathological changes of skin tissue caused by ultraviolet radiation and the arrangement of collagen were observed by Hematoxylin-Eosin (HE) staining and scanning electron microscopy (SEM). Interleukin 1ß (IL-1ß), IL-6, and IL-10 were detected using the quantitative real-time reverse transcription-polymerase chain reaction (qPCR) and Enzyme Linked Immunosorbent Assay (ELISA). The concentration and expression of these proinflammatory cytokines was associated with the presence of nuclear factor (NF)-κB. The results show that MAA compounds from Porphyra yezoensis could suppress UV-induced photoaging of skin by inhibiting the reduction of endogenous antioxidant enzymes. Compared to the control group, the concentrations of SOD, GSH-Px, and CAT increased significantly in skin tissue homogenate following the external administration of MAAs (p < 0.05, p < 0.01), while the content of MDA decreased significantly (p < 0.05). Meanwhile, the administration of MAAs was associated with down-regulations in the concentration and mRNA expression of NF-κB, IL-1ß, IL-6, and IL-10. The results suggest that MAAs could protect skin from photodamage by increasing antioxidant enzyme activities and inhibiting inflammation.


Assuntos
Aminoácidos/farmacologia , Cicloexanonas/farmacologia , Cicloexilaminas/farmacologia , Glicina/análogos & derivados , Substâncias Protetoras/farmacologia , Dermatopatias/tratamento farmacológico , Raios Ultravioleta/efeitos adversos , Animais , Antioxidantes/metabolismo , Citocinas/metabolismo , Glicina/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , RNA Mensageiro/metabolismo , Pele/efeitos dos fármacos , Dermatopatias/metabolismo
13.
Infect Immun ; 87(11)2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31405956

RESUMO

Coxiella burnetii is an intracellular bacterium that causes query, or Q fever, a disease that typically manifests as a severe flu-like illness. The initial target of C. burnetii is the alveolar macrophage. Here, it regulates vesicle trafficking pathways and fusion events to establish a large replication vacuole called the Coxiella-containing vacuole (CCV). Similar to a phagolysosome, the CCV has an acidic pH and contains lysosomal hydrolases obtained via fusion with late endocytic vesicles. Lysosomal hydrolases break down various lipids, carbohydrates, and proteins; thus, it is assumed C. burnetii derives nutrients for growth from these degradation products. To investigate this possibility, we utilized a GNPTAB-/- HeLa cell line that lacks lysosomal hydrolases in endocytic compartments. Unexpectedly, examination of C. burnetii growth in GNPTAB-/- HeLa cells revealed replication and viability are not impaired, indicating C. burnetii does not require by-products of hydrolase degradation to survive and grow in the CCV. However, although bacterial growth was normal, CCVs were abnormal, appearing dark and condensed rather than clear and spacious. Lack of degradation within CCVs allowed waste products to accumulate, including intraluminal vesicles, autophagy protein LC3, and cholesterol. The build-up of waste products coincided with an altered CCV membrane, where LAMP1 was decreased and CD63 and LAMP1 redistributed from a punctate to uniform localization. This disruption of CCV membrane organization may account for the decreased CCV size due to impaired fusion with late endocytic vesicles. Collectively, these results demonstrate lysosomal hydrolases are not required for C. burnetii survival and growth but are needed for normal CCV development. These data provide insight into mechanisms of CCV biogenesis while raising the important question of how C. burnetii obtains essential nutrients from its host.


Assuntos
Hidrolases/metabolismo , Aminoácidos/administração & dosagem , Aminoácidos/farmacologia , Catepsina D , Proliferação de Células , Colesterol/metabolismo , Coxiella burnetii , Meios de Cultura , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Lisossomos , Macrolídeos/farmacologia , Viabilidade Microbiana
14.
Animal ; 13(11): 2727-2735, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31407650

RESUMO

The gut is composed of a single layer of intestinal epithelial cells and plays important roles in the digestion and absorption of nutrients, immune and barrier functions and amino acid metabolism. Weaning stress impairs piglet intestinal epithelium structural and functional integrities, which results in reduced feed intake, growth rates and increased morbidity and mortality. Several measures are needed to maintain swine gut development and growth performance after weaning stress. A large body of evidence indicates that, in weaning piglets, glutamine, a functional amino acid, may improve growth performance and intestinal morphology, reduce oxidative damage, stimulate enterocyte proliferation, modulate cell survival and death and enhance intestinal paracellular permeability. This review focuses on the effects of glutamine on intestinal health in piglets. The aim is to provide evidentiary support for using glutamine as a feed additive to alleviate weaning stress.


Assuntos
Suplementos Nutricionais/análise , Glutamina/farmacologia , Suínos/fisiologia , Aminoácidos/farmacologia , Ração Animal/análise , Animais , Dieta/veterinária , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Permeabilidade/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Suínos/crescimento & desenvolvimento , Desmame
15.
ACS Appl Mater Interfaces ; 11(37): 33559-33572, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31424189

RESUMO

An optimum hydrophilic/hydrophobic balance has been recognized as a crucial parameter in designing cationic polymers that mimic antimicrobial peptides (AMPs). To date, this balance was achieved either by hydrophilicity variation through altering the nature and the number of cationic charges or by hydrophobicity modulation through incorporation of alkyl groups of different chain lengths. However, how the hydrophobicity variation through AMPs' building blocks-amino acids-influences the antibacterial efficacy of AMP-mimicking cationic polymers has rarely been explored. Toward this goal, herein we report a class of amino acid conjugated polymers (ACPs) with tunable antibacterial activity through a simple post-polymer-functionalization strategy. Our polymeric design comprised a permanent cationic charge in every repeating unit, whereby the hydrophobicity was tuned through incorporation of different amino acids. Our results revealed that the amino acid alteration has a strong influence on antibacterial efficacy. Upon increasing the amino acid side-chain hydrophobicity, both the antibacterial activity (against broad spectrum of bacteria) and toxicity increased. However, the distinct feature of this class of polymers was their good activity against Acinetobacter baumannii-the top most critical pathogen according to WHO, which has created an alarming situation worldwide, causing the majority of infections in humans. A nontoxic (no hemolysis even at 1000 µg/mL) ACP including a glycine residue (ACP-1 (Gly)) showed very good activity (MIC = 8-16 µg/mL) against both drug-sensitive and drug-resistant strains of A. baumannii, including clinical isolates. This polymer not only was rapidly bactericidal against growing planktonic A. baumannii but also killed nondividing stationary-phase cells instantaneously (<2 min). Moreover, it eradicated the established biofilm formed by drug-resistant A. baumannii clinical isolates. No propensity for bacterial resistance development against this polymer was seen even after 14 continuous passages. Taken together, the results highlight that hydrophobicity modulation through incorporation of amino acids in cationic polymers will provide a significant opportunity in designing new ACPs with potent antibacterial activity and minimum toxicity toward mammalian cells. More importantly, the excellent anti-A. baumannii efficacy of the optimized lead polymer indicates its immense potential for being developed as therapeutic agent.


Assuntos
Acinetobacter baumannii/fisiologia , Antibacterianos , Biofilmes/efeitos dos fármacos , Materiais Biomiméticos , Farmacorresistência Bacteriana/efeitos dos fármacos , Polímeros , Aminoácidos/química , Aminoácidos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Células HEK293 , Humanos , Polímeros/química , Polímeros/farmacologia
16.
Amino Acids ; 51(9): 1337-1351, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31428912

RESUMO

The application of high concentrations of taurine induces long-lasting potentiation of synaptic responses and axon excitability. This phenomenon seems to require the contribution of a transport system with a low affinity for taurine. The prototypic taurine transporter TauT (SLC6A6) was discarded by experimental evidence obtained in TauT-KO mice. The purpose of the present study was to determine whether the proton-coupled amino acid transporter 1 (PAT1; SLC36A1) which is a transport system with low affinity and high capacity for a great variety of amino acids including taurine, contributes to the taurine-induced synaptic potentiation. In rat hippocampal slices, the application of several amino acids (L- and D-alanine, L-glutamine, ß-guanidinopropionic acid, glycine, L-histidine, L- and D-serine, sarcosine, L- and D-threonine) imitated the synaptic potentiation induced by taurine. The magnitude of the potentiation caused by some of these amino acids was even greater than that induced by taurine. By contrast, the application of other amino acids (L-arginine, betaine, L-leucine, L-methionine, L- and D-proline, and L-valine) did not induce potentiation. The behaviour of these different amino acids on synaptic potentiation is not compatible with a role of PAT1 in synaptic potentiation. There was a positive correlation between the accumulation of the different amino acids in the slice and the magnitude of synaptic potentiation induced by them. Some of the amino acids inducing synaptic potentiation, like taurine and L-threonine, also increased electrical resistance of the slice, whereas L-leucine did not modify this parameter. Modifications induced by either taurine or L-threonine in synaptic potentiation, slice resistance and amino acid accumulation were dependent on extracellular chloride concentration. These findings support the idea that the accumulation of amino acids throughout the action of transporters causes cell swelling enhancing the electrical resistance of the slice, which by itself could be sufficient to increase field synaptic potentials.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Aminoácidos/metabolismo , Hipocampo/fisiologia , Simportadores/metabolismo , Potenciais Sinápticos , Aminoácidos/química , Aminoácidos/farmacologia , Animais , Impedância Elétrica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Taurina/metabolismo , Taurina/farmacologia , Treonina/metabolismo , Treonina/farmacologia
17.
J Enzyme Inhib Med Chem ; 34(1): 1178-1185, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31282230

RESUMO

The activation of the ß-class carbonic anhydrases (CAs, EC 4.2.1.1) from the bacteria Brucella suis and Francisella tularensis with amine and amino acids was investigated. BsuCA 1 was sensitive to activation with amino acids and amines, whereas FtuCA was not. The most effective BsuCA 1 activators were L-adrenaline and D-Tyr (KAs of 0.70-0.95 µM). L-His, L-/D-Phe, L-/D-DOPA, L-Trp, L-Tyr, 4-amino-L-Phe, dopamine, 2-pyridyl-methylamine, D-Glu and L-Gln showed activation constants in the range of 0.70-3.21 µM. FtuCA was sensitive to activation with L-Glu (KA of 9.13 µM). Most of the investigated compounds showed a weak activating effect against FtuCA (KAs of 30.5-78.3 µM). Many of the investigated amino acid and amines are present in high concentrations in many tissues in vertebrates, and their role in the pathogenicity of the two bacteria is poorly understood. Our study may bring insights in processes connected with invasion and pathogenic effects of intracellular bacteria.


Assuntos
Aminas/farmacologia , Aminoácidos/farmacologia , Brucella suis/enzimologia , Anidrases Carbônicas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Francisella tularensis/enzimologia , Aminas/química , Aminoácidos/química , Anidrases Carbônicas/genética , Relação Estrutura-Atividade
18.
Biomater Sci ; 7(9): 3675-3682, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31322153

RESUMO

Proteins are fragile such that even freezing, drying and dehydration may induce their denaturation, aggregation, and activity loss. To protect proteins from these kinds of damage, we prepared two types of amino acid polymers, poly-(l-glutamate)-r-poly-(l-lysine) (PLG-r-PLL) and poly-l-glutamate (PLG), from the efficient ring-opening polymerization of α-amino acid N-carboxyanhydride (NCA) using lithium hexamethyldisilazide (LiHMDS) as the initiator. ß-galactosidase (ß-Gal) was used in this study to examine the protein protecting effect of the synthesized amino acid polymers during lyophilization. The results indicate that both PLG-r-PLL and PLG exert significant protection on ß-Gal during lyophilization and improve the activity of the resulting protein from 40%, without using a protecting agent during lyophilization, to 80% of the original protein activity. Nevertheless, PLG generally performs better than PLG-r-PLL independent of the chain length. Our studies also show that PLG and PLG-r-PLL with a high content of PLG subunits display no observable cytotoxicity and hemolytic effect. Furthermore, dynamic light scattering (DLS) and transmission electron microscopy (TEM) characterization indicate that PLG protects ß-Gal upon lyophilization by preventing the aggregation of ß-Gal. Our studies demonstrate that amino acid polymers, such as PLG, can exert potent activity for protein stabilization. The easy operation of LiHMDS-initiated and efficient NCA polymerization implies the great potential of this strategy to prepare amino acid polymers quickly for the screening of protein stabilization and mechanism study.


Assuntos
Aminoácidos/farmacologia , Anidridos/farmacologia , Polímeros/farmacologia , beta-Galactosidase/metabolismo , Aminoácidos/química , Anidridos/química , Polímeros/síntese química , Polímeros/química , Estabilidade Proteica
19.
Eur J Med Chem ; 179: 567-575, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279291

RESUMO

In order to find new potential pesticide molecules with antifungal activities, we have designed and synthesized a series of amino acid-oriented poly-substituted tetramic acid derivatives, and evaluated their potential antifungal activities against six kinds of plant pathogenic fungus commonly found in agriculture systematically, including Phomopsis adianticola, Fusarium graminearum, Alternaria tenuis Nees, Magnaporthe oryzae, Gloeosporium theae-sinensis, Sclerotinia sclerotiorum. According to the preliminary bioassay studies, all tested molecules, especially compounds I-2, I-5, I-12, I-15, exhibited significant and broad-spectrum anti-fungal effect in vitro compared to the intermediates M-1, M-2, M-3 and hymexazol. What's more, the inhibition rate of compounds I-5, I-6, I-15 against Phomopsis adianticola reached 74.42%, 60.33%, 65.21%, as well as compounds I-3, I-5, I-15 against Sclerotinia sclerotiorum were 65.65%, 74.92%, 61.36%. Further investigation results indicated that compounds I-2, I-5, I-15 presented obviously inhibitory activities against Phomopsis adianticola compared with hymexazol, which might be considered as the basic active framework for further potential fungicides discovery.


Assuntos
Aminoácidos/farmacologia , Antifúngicos/farmacologia , Fungos/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Pirrolidinonas/farmacologia , Aminoácidos/química , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirrolidinonas/síntese química , Pirrolidinonas/química , Relação Estrutura-Atividade
20.
Int Rev Neurobiol ; 146: 83-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349933

RESUMO

There is a growing trend of hypertension among military and civilian populations due to lifetime stressful situations. If hypertension is uncontrolled it leads to development of diabetes and serious neurological complications. Most of the World populations live in temperate zone across the World. Thus, a possibility exists that these hypertensive and diabetic people may have external heat as potential risk factors for brain damage. We have seen brain edema and brain damage following exposure to heat stress at 38°C for 4h. A possibility exists that heat exposure in diabetic-hypertensive (DBHY) cases exacerbates exacerbation of brain pathology and edema formation. This hypothesis is examined in a rat model. The role of nitric oxide (NO) in exacerbation of HS-induced brain pathology was also evaluated using nitric oxide synthase (NOS) immunoreactivity. Hypertensive rats (produced by two-kidney one clip (2K1C) method) were made diabetic with streptozotocine (50mg/kg, i.p./day for 3days) treatment. After 6weeks, DBHY rats show 20-30mM/L Blood Glucose and hypertension (180-200mmHg). Subjection of these rats to 4h HS resulted in six- to eightfold higher BBB breakdown, brain edema formation and brain pathology. At this time, neuronal or inducible NOS expression was four- to sixfold higher in DBHY rats compared to controls. Interestingly, iNOS expression was higher than nNOS in DBHY rats. Cerebrolysin in high doses (10-mL/kg, i.v. instead of 5-mL/kg) induced significant neuroprotection and downregulation of nNOS and iNOS in DBHY animals whereas normal animals need only 5-mL/kg doses for this purpose. Our observations demonstrate that co-morbidly factors exacerbate brain damage in HS through NOS expression and require double dose of cerebrolysin for neuroprotection as compared to normal rats, not reported earlier.


Assuntos
Aminoácidos/farmacologia , Barreira Hematoencefálica/metabolismo , Edema Encefálico/fisiopatologia , Encéfalo/patologia , Diabetes Mellitus Experimental/prevenção & controle , Golpe de Calor/patologia , Golpe de Calor/fisiopatologia , Hipertensão/prevenção & controle , Óxido Nítrico Sintase/biossíntese , Animais , Encéfalo/metabolismo , Diabetes Mellitus Experimental/complicações , Hipertensão/complicações , Masculino , Neuroproteção/efeitos dos fármacos , Ratos , Estreptozocina , Regulação para Cima
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