Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Carbohydr Polym ; 332: 121909, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38431413

RESUMO

COMT inhibitors are commonly used to improve the effectiveness of levodopa in treating Parkinson's disease by inhibiting its conversion to 3-O-methyldopa. Because of the serious side effect of nitrocatechol COMT inhibitors, it is necessary to develop non-nitrocatechol COMT inhibitors with a higher safety profile. Heparin has been observed to bind to COMT. However, the exact functional significance of this interaction is not fully understood. In this study, the contribution of different substitution of heparin to its binding with COMT was investigated. In vitro and in vivo, heparin oligosaccharides can bind to COMT and inhibit its activity. Furthermore, we enriched the functional heparin oligosaccharides that bind to COMT and identified the sequence UA2S-GlcN(S/Ac)6(S/H)-UA2S-GlcNS6(S/H)-UA2(S/H)-GlcNS6S as the characteristic structural domain of these functional oligosaccharides. This study has elucidated the relationship between the structure of heparin oligosaccharides and their activity against COMT, providing valuable insights for the development of non-nitrocatechol COMT inhibitors with improved safety and efficacy.


Assuntos
Catecol O-Metiltransferase , Doença de Parkinson , Humanos , Catecol O-Metiltransferase/metabolismo , Catecol O-Metiltransferase/uso terapêutico , Heparina/uso terapêutico , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Levodopa , Doença de Parkinson/tratamento farmacológico
2.
Int J Biol Macromol ; 259(Pt 1): 129032, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38159696

RESUMO

Heparin, a bio-molecule with the highest negative charge density, is pharmaceutically important to prevent SARS-CoV-2 infection due to its strong competitive binding to spike protein compared with cellular heparan sulfate, which was confirmed as a co-receptor for virus-host cell interaction. Hence, the refined structural characterization of heparin targeting viral protein-HS interaction was significant for developing antiviral pharmaceuticals. In our study, heparin oligomers (dp ≥ 4) were prepared using heparinase I. The affinity oligosaccharides binding to Omicron spike protein RBD were separated by affinity chromatography and size exclusion chromatography. HILIC-ESI-FTMS was used for chain mapping analysis. The basic building blocks were analyzed and the binding domain sequence was produced by Seq-GAG software and further measured by SAX chromatography. As results, heparin octasaccharide was found with significantly higher binding ability than hexasaccharide and tetrasaccharide, and the octasaccharide [ΔUA-GlcNS6S-GlcA-GlcNS6S-IdoA2S-GlcNS6S-IdoA2S-GlcNS6S] with 12 sulfate groups showed high binding to RBD. The mechanism of this structurally well-defined octasaccharide binding to RBD was further investigated by molecular docking. The affinity energy of optimal pose was -6.8 kcal/mol and the basic amino acid residues in RBD sequence (Arg403, Arg452, Arg493 and His505) were identified as the major contribution factor to interacting with sulfate/carboxyl groups on saccharide chain. Our study demonstrated that heparin oligosaccharide with well-defined structure could be potentially developed as anti-SARS-CoV-2 drugs.


Assuntos
COVID-19 , Heparina , Humanos , Heparina/química , SARS-CoV-2/metabolismo , Simulação de Acoplamento Molecular , Glicoproteína da Espícula de Coronavírus/química , Oligossacarídeos/química , Sulfatos , Ligação Proteica
3.
Se Pu ; 41(11): 995-1001, 2023 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-37968818

RESUMO

The aim of this study is to explore differences in the peptidomics of Saccharomyces pastorianus protein hydrolysates treated with different enzymes. Briefly, differences in the peptide fingerprints and active peptides of neutral protease/papain-hydrolyzed S. pastorianus were analyzed using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) combined with PEAKS Online 1.7 analysis software, Peptide Ranker, and the BIOPEP database. Compared to traditional databases, the PEAKS Online uses de novo sequencing for analysis to obtain oligopeptides smaller than pentapeptides. It provides more comprehensive data of the peptide sample. In this study, enzymatic hydrolysates of S. pastorianus protein were prepared under the optimum conditions of neutral protease and papain respectively. In total, 7221 and 7062 polypeptides were identified in the hydrolysates of neutral protease and papain, respectively; among these polypeptides, 980 were common to the two enzymes. The 6241 and 6082 unique peptides found in the hydrolysates of neutral protease and papain, respectively, indicated that the peptide fingerprints of the two hydrolysates are quite different. Peptide Ranker predicted that 3013 (41.73%) and 3095 (43.83%) peptides were potentially bioactive in the hydrolysates of neutral protease and papain, respectively. According to the BIOPEP database, neutral protease and papain contained 295 and 357 active peptides, respectively; these peptides were mainly composed of angiotensin converting enzyme (ACE) inhibitors and dipeptidyl peptidase IV inhibitors and antioxidant peptides. The number of active peptides in the hydrolysate of papain was higher than that in the hydrolysate of neutral protease, but the total ion intensity of active peptides in the former was lower than that in the latter. This study revealed the influence of protease type on the composition of enzymatic hydrolysates from S. pastorianus protein. The above results provide a reference for the development of functional products of S. pastorianus protein peptides and the high-value utilization of yeast resources.


Assuntos
Papaína , Hidrolisados de Proteína , Papaína/química , Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologia , Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Peptídeos/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Hidrólise
4.
Anal Chem ; 94(40): 13987-13994, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36183273

RESUMO

Glycosaminoglycans (GAGs) have high negative charge and are biologically and pharmaceutically important because their high charge promotes a strong interaction with many proteins. Due to the inherent heterogeneity of GAGs, multiple oligosaccharides, containing certain common domains, often can interact with clusters of basic amino acid residues on a target protein. The specificity of many GAG-protein interactions remains undiscovered since there is insufficient structural information on the interacting GAGs. Herein, we establish a cluster sequencing strategy to simultaneously deduce all major sequences of the affinity GAG oligosaccharides, leading to a definition of the consensus sequence they share that corresponds to the specific binding domain for the target protein. As a proof of concept, antithrombin III-binding oligosaccharides were examined, resulting in a heptasaccharide domain containing the well-established anticoagulant pentasaccharide sequence. Repeating this approach, a new pentasaccharide domain was discovered corresponding to the heparin motif responsible for binding interferon-γ (IFNγ). Our strategy is fundamentally important for the discovery of saccharide sequences needed in the development of novel GAG-based therapeutics.


Assuntos
Antitrombina III , Heparina , Aminoácidos Básicos/metabolismo , Anticoagulantes , Antitrombina III/química , Antitrombina III/metabolismo , Glicosaminoglicanos/química , Heparina/química , Interferon gama , Oligossacarídeos/química , Ligação Proteica
5.
Carbohydr Polym ; 275: 118694, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34742421

RESUMO

The elucidation of precise structure of fucoidan is essential for understanding their structure-function relationship and promoting the development of marine drugs. In this work, we firstly reported the oligosaccharide mapping of fucoidan from Holothuria floridana using a combination of hydrothermal depolymerization, hydrophilic interaction liquid chromatography (HILIC) coupled with electrospray mass spectrometry (ESI-FTMS) and high energy collision-induced dissociation (HCD-MS/MS) and 2D NMR analysis. With careful selection of fully deprotonated molecular ions of fucoidan oligosaccharides and their NaBD4 reduced alditols, HILIC-ESI-HCD-MS/MS provided structurally relevant glycosidic product ions with no sulfate loss for definitive assignment of sequence and sulfation pattern of all the oligosaccharides and their isomers from dp2 to dp7 from hydrothermal depolymerization. The oligosaccharide mapping clarified the structure of fucoidan with various oligosaccharide domains with 2,4-di-O-sulfated and 2-O sulfated fucose residues.


Assuntos
Oligossacarídeos/química , Polissacarídeos/química , Pepinos-do-Mar/química , Animais , Cromatografia Líquida/métodos , Holothuria/química , Interações Hidrofóbicas e Hidrofílicas , Isomerismo , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Polimerização , Espectrometria de Massas por Ionização por Electrospray/métodos , Sulfatos/química , Espectrometria de Massas em Tandem/métodos
6.
Food Funct ; 12(19): 9087-9097, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34388231

RESUMO

Antibiotic abuse can lead to gut microbiota disturbance and intestinal inflammation, which in turn may lead to serious inflammatory bowel disease and metabolic syndromes. To investigate the effect of fucoidan on alleviation of the side effects of antibiotics and its structure-activity relationship, we compared the effects of two fucoidan fractions with medium and low molecular weights (MF and LF) from Laminaria japonica on microbiota dysbiosis, colonic inflammation and intestinal mucosal damage in a cefoperazone-induced intestinal injury mouse model. Our results showed that oral administration of 200 mg kg-1 LF (Mw = 1.13 kDa) and MF (Mw = 26.7 kDa) together with 100 mg kg-1 cefoperazone for 10 days could significantly alleviate weight loss, colon shortening and enlargement, mucosal structural damage in the small intestine, cecum and colon induced by cefoperazone in mice. Meanwhile, LF and MF also significantly suppressed the overproduction of TNF-α, IFN-γ, and IL-6 in the colon; however, LF can restore the decrease in the levels of TNF-α and IL-6 in the small intestine and the decrease in the levels of TNF-α, IFN-γ, and IL-6 in the cecum induced by cefoperazone in mice. We found that the molecular weight of fucoidan plays an important role in the regulation of the gut microbiota in antibiotic-treated mice. Interestingly, fucoidans with different molecular weights resulted in quite different caecal microbiota communities. MF exhibited a much better effect on the restoration of the gut microbiota community richness and diversity and the beneficial bacterium Muribaculaceae. However, LF resulted in the dominance of bacteria including Staphylococcus in cefoperazone treated mice, without an increase in the community richness and diversity of caecal microbiota. In the LF and MF treated mice, an increase in the abundance of beneficial bacteria, Muribaculaceae, Acinetobacter_lwoffii and Alloprevotella, and a decrease in the abundance of harmful bacteria, e.g., Parasutterella, Helicobacter and Enterococcus were also observed. Considering the negative effect of LF on the gut microbiota, MF with a molecular weight of 26.7 kDa seemed to be a more suitable choice of prebiotics for patients receiving cefoperazone treatment.


Assuntos
Antibacterianos/efeitos adversos , Cefoperazona/efeitos adversos , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal , Polissacarídeos/administração & dosagem , Prebióticos , Animais , Ceco/microbiologia , Citocinas/metabolismo , Disbiose/etiologia , Disbiose/patologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Inflamação , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Intestinos/metabolismo , Intestinos/microbiologia , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Polissacarídeos/química , Polissacarídeos/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...