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1.
Chem Sci ; 13(21): 6233-6243, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35733906

RESUMO

Modulation of N-glycosylation using human Golgi α-mannosidase II (α-hGMII) inhibitors is a potential anticancer approach, but the clinical utility of current α-hGMII inhibitors is limited by their co-inhibition of human lysosomal α-mannosidase (α-hLM), resulting in abnormal storage of oligomannoses. We describe the synthesis and screening of a small library of novel bicyclic iminosugar-based scaffolds, prepared via natural product-inspired combinatorial chemistry (NPICC), which resulted in the identification of a primary α-hGMII inhibitor with 13.5-fold selectivity over α-hLM. Derivatization of this primary inhibitor using computation-guided synthesis (CGS) yielded an advanced α-hGMII inhibitor with nanomolar potency and 106-fold selectivity over α-hLM. In vitro studies demonstrated its N-glycan modulation and inhibitory effect on hepatocellular carcinoma (HCC) cells. In vivo studies confirmed its encouraging anti-HCC activity, without evidence of oligomannose accumulation.

2.
J Biomed Sci ; 26(1): 97, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31861989

RESUMO

BACKGROUND: Dectin-2, which is a C-type lectin, interacts with the house dust mite (HDM) Dermatophagoides pteronyssinus allergen. This study aimed to investigate whether Dectin-2 blockade by antagonistic monoclonal antibodies (MoAbs) attenuates HDM-induced allergic responses. METHODS: Two anti-Dectin-2 MoAbs were generated and validated for specific binding to Dectin-2 Fc fusion protein (Dectin-2.Fc) and inhibition of Dectin-2.Fc/HDM interaction. Patients with asthma exhibiting high titers of anti-D. pteronyssinus IgE were enrolled. Peripheral blood mononuclear cells with depleted CD14+ monocytes were obtained from these patients and co-cultured with autologous monocyte-derived conventional dendritic cells in the presence of D. pteronyssinus or its group 2 allergens (Der p 2). Interleukin (IL)-5 and IL-13 levels in the culture supernatants were determined using ELISA in the presence or absence of anti-Dectin-2 MoAbs. RESULTS: Two MoAbs, 6A4G7 and 17A1D10, showed specific binding to recombinant Dectin-2.Fc and inhibited HDM binding to Dectin-2.Fc. Both anti-Dectin-2 MoAbs inhibited IL-5 and IL-13 production in co-cultures with Der p 2 stimulation in a dose-dependent manner. 6A4G7 and 17A1D10 (3 µg/mL) significantly inhibited Der p 2-induced (3 µg/mL) IL-5 production by 69.7 and 86.4% and IL-13 production by 84.0 and 81.4%, respectively. Moreover, this inhibitory effect of the two MoAbs remained significant in the presence of D. pteronyssinus. CONCLUSIONS: Anti-Dectin-2 MoAbs significantly inhibited HDM-induced allergic responses in vitro and therefore have the potential to become therapeutic agents in mite-induced allergic diseases.


Assuntos
Anticorpos Bloqueadores/imunologia , Asma/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Lectinas Tipo C/imunologia , Leucócitos Mononucleares/imunologia , Pyroglyphidae/imunologia , Adulto , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Células Th2
3.
J Am Chem Soc ; 140(8): 2752-2755, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29411975

RESUMO

The rise of antibiotic resistance has created a mounting crisis across the globe and an unmet medical need for new antibiotics. As part of our efforts to develop new antibiotics to target the uncharted surface bacterial transglycosylase, we report an affinity-based ligand screen method using penicillin-binding proteins immobilized on beads to selectively isolate the binders from complex natural products. In combination with mass spectrometry and assays with moenomycin A and salicylanilide analogues (1-10) as reference inhibitors, we isolated four potent antibacterials confirmed to be benastatin derivatives (11-13) and albofungin (14). Compounds 11 and 14 were effective antibiotics against a broad-spectrum of Gram-positive and Gram-negative bacteria, including Acinetobacter baumannii, Clostridium difficile, Staphylococcus aureus, and drug-resistant strains with minimum inhibitory concentrations in the submicromolar to nanomolar range.


Assuntos
Antibacterianos/farmacologia , Bambermicinas/farmacologia , Inibidores Enzimáticos/farmacologia , Glicosiltransferases/antagonistas & inibidores , Salicilanilidas/farmacologia , Xantenos/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/enzimologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Bambermicinas/química , Bambermicinas/isolamento & purificação , Clostridioides difficile/efeitos dos fármacos , Clostridioides difficile/enzimologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Glicosiltransferases/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Salicilanilidas/química , Salicilanilidas/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Relação Estrutura-Atividade , Xantenos/química , Xantenos/isolamento & purificação
4.
Chem Asian J ; 13(6): 686-700, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29380519

RESUMO

LecA is a galactose-binding tetrameric lectin from Pseudomonas aeruginosa involved in infection and biofilm formation. The emergent antibiotic resistance of P. aeruginosa has made LecA a promising pharmaceutical target to treat such infections. To develop LecA inhibitors, we exploit the unique helical structure of polyproline peptides to create a scaffold that controls the galactoside positions to fit their binding sites on LecA. With a modular scaffold design, both the galactoside ligands and the inter-ligand distance can be altered conveniently. We prepared scaffolds with spacings of 9, 18, 27, and 36 Šfor ligand conjugation and found that glycopeptides with galactosides ligands three helical turns (27 Å) apart best fit LecA. In addition, we tested different galactose derivatives on the selected scaffold (27 Å) to improve the binding avidity to LecA. The results validate a new multivalent scaffold design and provide useful information for LecA inhibitor development.


Assuntos
Adesinas Bacterianas/metabolismo , Galactosídeos/farmacologia , Peptídeos/farmacologia , Pseudomonas aeruginosa/química , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Galactosídeos/síntese química , Galactosídeos/química , Ligantes , Estrutura Molecular , Peptídeos/química , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície
5.
Biochemistry ; 56(40): 5417-5427, 2017 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-28872301

RESUMO

Bacteria cell walls contain many repeating glycan structures, such as peptidoglycans, lipopolysaccharides, teichoic acids, and capsular polysaccharides. Their synthesis starts in the cytosol, and they are constructed from a glycan lipid carrier, undecaprenyl phosphate (C55P), which is essential for cell growth and survival. The lipid derivative undecaprenol (C55OH) is predominant in many Gram-positive bacteria but has not been detected in Gram-negative bacteria; its origin and role have thus remained unknown. Recently, a homologue of diacylglycerol kinase (DgkA) in Escherichia coli (E. coli) was demonstrated to be an undecaprenol kinase (UK) in the Gram-positive bacterium Streptococcus mutans (S. mutans). In this study, we found that S. mutans UK was not only an undecaprenol kinase but also a Mg-ADP-dependent undecaprenyl phosphate phosphatase (UpP), catalyzing the hydrolysis of C55P to C55OH and a free inorganic phosphate. Furthermore, the naturally undetectable C55OH was observed in E. coli cells expressing S. mutans dgkA, supporting the phosphatase activity of UK/UpP in vivo. These two activities were indispensable to each other and utilized identical essential residues binding to their substrates, suggesting that both activities share the same active site and might involve a direct phosphoryl transfer mechanism. This study revealed a unique membrane enzyme displaying bifunctional activities determined by substrate binding and C55OH production. The reciprocal conversion of C55P and the undecaprenol pool efficiently regulate cell wall synthesis, especially in Gram-positive bacteria.


Assuntos
Metabolismo dos Lipídeos , Monoéster Fosfórico Hidrolases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfatos de Poli-Isoprenil/metabolismo , Streptococcus mutans/enzimologia , Difosfato de Adenosina/metabolismo , Modelos Moleculares , Monoéster Fosfórico Hidrolases/química , Fosforilação , Estrutura Secundária de Proteína , Especificidade por Substrato
6.
Chem Commun (Camb) ; 53(4): 771-774, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27999831

RESUMO

Lipid II analogues bearing major modifications on the second sugar (GlcNAc) were synthesized and evaluated for their substrate activity toward TGases. Unexpectedly, N-deacetyled lipid II decreased its activity dramatically, and the C4-axial OH lipid II became an inhibitor (IC50 = 8 µM) with an approximately 14-fold increase in binding affinity toward TGase (25 vs. 27).


Assuntos
Clostridioides difficile/enzimologia , Inibidores Enzimáticos/farmacologia , Escherichia coli/enzimologia , Lipídeos/farmacologia , Peptidoglicano Glicosiltransferase/antagonistas & inibidores , Açúcares/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Lipídeos/química , Peptidoglicano Glicosiltransferase/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Açúcares/síntese química , Açúcares/química
7.
Sci Rep ; 6: 31579, 2016 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-27531195

RESUMO

Systematic structural modifications of the muramic acid, peptide, and nucleotide moieties of Park's nucleotide were performed to investigate the substrate specificity of B. subtilis MraY (MraYBS). It was found that the simplest analogue of Park's nucleotide only bearing the first two amino acids, l-alanine-iso-d-glutamic acid, could function as a MraYBS substrate. Also, the acid group attached to the Cα of iso-d-glutamic acid was found to play an important role for substrate activity. Epimerization of the C4-hydroxyl group of muramic acid and modification at the 5-position of the uracil in Park's nucleotide were both found to dramatically impair their substrate activity. Unexpectedly, structural modifications on the uracil moiety changed the parent molecule from a substrate to an inhibitor, blocking the MraYBS translocation. One unoptimized inhibitor was found to have a Ki value of 4 ± 1 µM against MraYBS, more potent than tunicamycins.


Assuntos
Proteínas de Bactérias/metabolismo , Nucleotídeos/metabolismo , Transferases/metabolismo , Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Testes de Sensibilidade Microbiana , Conformação de Ácido Nucleico , Nucleotídeos/química , Staphylococcus aureus/efeitos dos fármacos , Especificidade por Substrato , Transferases/antagonistas & inibidores , Transferases/química , Transferases (Outros Grupos de Fosfato Substituídos)
8.
J Am Chem Soc ; 136(48): 16844-53, 2014 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-25371992

RESUMO

Globo H-based therapeutic cancer vaccines have been tested in clinical trials for the treatment of late stage breast, ovarian, and prostate cancers. In this study, we explored Globo H analogue antigens with an attempt to enhance the antigenic properties in vaccine design. The Globo H analogues with modification at the reducing or nonreducing end were synthesized using chemoenzymatic methods, and these modified Globo H antigens were then conjugated with the carrier protein diphtheria toxoid cross-reactive material (CRM) 197 (DT), and combined with a glycolipid C34 as an adjuvant designed to induce a class switch to form the vaccine candidates. After Balb/c mice injection, the immune response was studied by a glycan array and the results showed that modification at the C-6 position of reducing end glucose of Globo H with the fluoro, azido, or phenyl group elicited IgG antibody response to specifically recognize Globo H (GH) and the GH-related epitopes, stage-specific embryonic antigen 3 (SSEA3) (also called Gb5) and stage-specific embryonic antigen 4 (SSEA4). However, only the modification of Globo H with the azido group at the C-6 position of the nonreducing end fucose could elicit a strong IgG immune response. Moreover, the antibodies induced by these vaccines were shown to recognize GH expressing tumor cells (MCF-7) and mediate the complement-dependent cell cytotoxicity against tumor cells. Our data suggest a new potential approach to cancer vaccine development.


Assuntos
Antígenos Glicosídicos Associados a Tumores/química , Antígenos Glicosídicos Associados a Tumores/imunologia , Vacinas Anticâncer/imunologia , Animais , Antígenos Glicosídicos Associados a Tumores/farmacologia , Vacinas Anticâncer/química , Vacinas Anticâncer/farmacologia , Configuração de Carboidratos , Proliferação de Células/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Oxirredução , Relação Estrutura-Atividade
9.
Angew Chem Int Ed Engl ; 53(31): 8060-5, 2014 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-24990652

RESUMO

The emergence of antibiotic resistance has prompted active research in the development of antibiotics with new modes of action. Among all essential bacterial proteins, transglycosylase polymerizes lipid II into peptidoglycan and is one of the most favorable targets because of its vital role in peptidoglycan synthesis. Described in this study is a practical enzymatic method for the synthesis of lipid II, coupled with cofactor regeneration, to give the product in a 50-70% yield. This development depends on two key steps: the overexpression of MraY for the synthesis of lipid I and the use of undecaprenol kinase for the preparation of polyprenol phosphates. This method was further applied to the synthesis of lipid II analogues. It was found that MraY and undecaprenol kinase can accept a wide range of lipids containing various lengths and configurations. The activity of lipid II analogues for bacterial transglycolase was also evaluated.


Assuntos
Enzimas/química , Uridina Difosfato Ácido N-Acetilmurâmico/análogos & derivados , Uridina Difosfato Ácido N-Acetilmurâmico/síntese química
10.
J Am Chem Soc ; 135(45): 17078-89, 2013 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-24131464

RESUMO

The emergence of antibiotic resistance has prompted scientists to search for new antibiotics. Transglycosylase (TGase) is an attractive target for new antibiotic discovery due to its location on the outer membrane of bacteria and its essential role in peptidoglycan synthesis. Though there have been a few molecules identified as TGase inhibitors in the past thirty years, none of them have been developed into antibiotics for humans. The slow pace of development is perhaps due to the lack of continuous, quantitative, and high-throughput assay available for the enzyme. Herein, we report a new continuous fluorescent assay based on Förster resonance energy transfer, using lipid II analogues with a dimethylamino-azobenzenesulfonyl quencher in the lipid chain and a coumarin fluorophore in the peptide chain. During the process of transglycosylation, the quencher-appended polyprenol is released and the fluorescence of coumarin can be detected. Using this system, the substrate specificity and affinity of lipid II analogues bearing various numbers and configurations of isoprene units were investigated. Moreover, the inhibition constants of moenomycin and two previously identified small molecules were also determined. In addition, a high-throughput screening using the new assay was conducted to identify potent TGase inhibitors from a 120,000 compound library. This new continuous fluorescent assay not only provides an efficient and convenient way to study TGase activities, but also enables the high-throughput screening of potential TGase inhibitors for antibiotic discovery.


Assuntos
Bactérias/enzimologia , Transferência Ressonante de Energia de Fluorescência/métodos , Peptidoglicano Glicosiltransferase/metabolismo , Cumarínicos/química , Cumarínicos/metabolismo , Ensaios Enzimáticos/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Peptidoglicano Glicosiltransferase/antagonistas & inibidores , Uridina Difosfato Ácido N-Acetilmurâmico/análogos & derivados , Uridina Difosfato Ácido N-Acetilmurâmico/química , Uridina Difosfato Ácido N-Acetilmurâmico/metabolismo
12.
J Am Chem Soc ; 135(30): 11140-50, 2013 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-23819648

RESUMO

We have successfully developed a [1+2+3] one-pot strategy to synthesize the RM2 antigen hexasaccharide that was proposed to be a prostate tumor antigen. The structure of the synthetic product was verified by NMR analysis and antibody binding assay using a glycan microarray. In addition, the synthetic antigen was conjugated to a mutated diphtheria toxin (DT, CRM197) with different copy numbers and adjuvant combinations to form the vaccine candidates. After vaccination in mice, we used glycan microarrays to monitor their immune response, and the results indicated that, when one molecule of DT was incorporated with 4.7 molecules of RM2 on average (DT-RM4.7) and adjuvanted with the glycolipid C34, the combination exhibited the strongest anti-RM2 IgG titer. Moreover, the induced mouse antibodies mediated effective complement-dependent cytotoxicity (CDC) against the prostate cancer cell line LNCap.


Assuntos
Antígenos Glicosídicos Associados a Tumores/química , Antígenos Glicosídicos Associados a Tumores/imunologia , Vacinas Anticâncer/síntese química , Vacinas Anticâncer/imunologia , Neoplasias da Próstata/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Antígenos Glicosídicos Associados a Tumores/metabolismo , Vacinas Anticâncer/química , Vacinas Anticâncer/metabolismo , Técnicas de Química Sintética , Toxina Diftérica/genética , Toxina Diftérica/metabolismo , Galactose/metabolismo , Glicolipídeos/metabolismo , Masculino , Camundongos , Mutação , Oligossacarídeos/metabolismo , Vacinas Sintéticas
14.
Proc Natl Acad Sci U S A ; 110(7): 2517-22, 2013 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-23355685

RESUMO

Globo H (GH) is a hexasaccharide specifically overexpressed on a variety of cancer cells and therefore, a good candidate for cancer vaccine development. To identify the optimal carrier and adjuvant combination, we chemically synthesized and linked GH to a carrier protein, including keyhole limpet hemocyanion, diphtheria toxoid cross-reactive material (CRM) 197 (DT), tetanus toxoid, and BSA, and combined with an adjuvant, and it was administered to mice for the study of immune response. Glycan microarray analysis of the antiserum obtained indicated that the combination of GH-DT adjuvanted with the α-galactosylceramide C34 has the highest enhancement of anti-GH IgG. Compared with the phase III clinical trial vaccine, GH-keyhole limpet hemocyanion/QS21, the GH-DT/C34 vaccine elicited more IgG antibodies, which are more selective for GH and the GH-related epitopes, stage-specific embryonic antigen 3 (SSEA3) and SSEA4, all of which were specifically overexpressed on breast cancer cells and breast cancer stem cells with SSEA4 at the highest level (>90%). We, therefore, further developed SSEA4-DT/C34 as a vaccine candidate, and after immunization, it was found that the elicited antibodies are also IgG-dominant and very specific for SSEA4.


Assuntos
Antígenos Glicosídicos Associados a Tumores/farmacologia , Proteínas de Bactérias/imunologia , Neoplasias da Mama/prevenção & controle , Vacinas Anticâncer/química , Antígenos Embrionários Estágio-Específicos/imunologia , Animais , Antígenos Glicosídicos Associados a Tumores/administração & dosagem , Antígenos Glicosídicos Associados a Tumores/química , Antígenos Glicosídicos Associados a Tumores/imunologia , Neoplasias da Mama/imunologia , Feminino , Citometria de Fluxo , Hemocianinas , Soros Imunes/análise , Imunoglobulina G/imunologia , Camundongos , Análise em Microsséries , Estrutura Molecular , Células-Tronco Neoplásicas/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Toxoide Tetânico
15.
Angew Chem Int Ed Engl ; 52(1): 366-70, 2013 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-23150231

RESUMO

The wizard of OS (resistance): the binding difference of neuraminidase inhibitors (zanamivir versus oseltamivir (OS)) was used to establish an assay to identify the influenza subtypes that are resistant to OS but still sensitive to zanamivir. This assay used a zanamivir-biotin conjugate to determine the OS susceptibility of a wide range of influenza viruses and over 200 clinical isolates.


Assuntos
Antivirais/química , Antivirais/farmacologia , Oseltamivir/química , Oseltamivir/farmacologia , Ligação Competitiva , Farmacorresistência Viral , Humanos , Vírus da Influenza A Subtipo H1N2/efeitos dos fármacos
16.
Chemistry ; 19(3): 834-8, 2013 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-23229320

RESUMO

Breaking down barriers: A rapid, inexpensive preparation of the structurally complex mycobacterial N-glycolyl Lipid I, Lipid II, and their analogues from a range of different synthetic N-glycolyl and N-glycinyl Park's nucleotides is described (see scheme). The biotransformations were catalyzed by a readily available biocatalyst obtained from a bacterial cell-free membrane fraction. The unnatural N-glycinyl Lipid II was found to be a substrate of Mycobacterium tuberculosis (Mtb) transglycosylase, PonA, and N-glycolyl Lipid I was a weak inhibitor against PonA.


Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Bactérias/metabolismo , Glicolipídeos/biossíntese , Mycobacterium tuberculosis/química , N-Acetilglucosaminiltransferases/metabolismo , Transferases/metabolismo , Biocatálise , Glicolipídeos/química , Glicolipídeos/metabolismo , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)
18.
J Med Chem ; 55(19): 8493-501, 2012 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-22963087

RESUMO

Influenza therapy with a single targeted compound is often limited in efficacy due to the rapidly developed drug resistance. Moreover, the uncontrolled virus-induced cytokines could cause the high mortality of human infected by H5N1 avian influenza virus. In this study, we explored the novel dual-targeted bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents. In particular, the caffeic acid (CA)-bearing zanamivir (ZA) conjugates ZA-7-CA (1) and ZA-7-CA-amide (7) showed simultaneous inhibition of influenza virus neuraminidase and suppression of pro-inflammatory cytokines. These ZA conjugates provided remarkable protection of cells and mice against influenza infections. Intranasal administration of low dosage (<1.2 µmol/kg/day) of ZA conjugates exhibited much greater effect than the combination therapy with ZA and the anti-inflammatory agents in protection of the lethally infected mice by H1N1 or H5N1 influenza viruses.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Antivirais/síntese química , Ácidos Cafeicos/síntese química , Zanamivir/análogos & derivados , Zanamivir/síntese química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antivirais/química , Antivirais/farmacologia , Ácidos Cafeicos/farmacologia , Linhagem Celular , Cães , Feminino , Vírus da Influenza A Subtipo H1N1 , Virus da Influenza A Subtipo H5N1 , Interferon gama/sangue , Interleucina-6/sangue , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Neuraminidase/antagonistas & inibidores , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/sangue , Zanamivir/farmacologia
19.
J Med Chem ; 55(20): 8657-70, 2012 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-23009169

RESUMO

Oseltamivir phosphonic acid (tamiphosphor, 3a), its monoethyl ester (3c), guanidino-tamiphosphor (4a), and its monoethyl ester (4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nanomolar to picomolar levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes, and human blood and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats, and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester 4c to phosphonic acid 4a was observed in rats after intravenous administration, but partial conversion of 4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use.


Assuntos
Acetamidas/síntese química , Alphainfluenzavirus/efeitos dos fármacos , Antivirais/síntese química , Betainfluenzavirus/efeitos dos fármacos , Cicloexenos/síntese química , Neuraminidase/antagonistas & inibidores , Acetamidas/farmacocinética , Acetamidas/farmacologia , Administração Oral , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Cicloexenos/farmacocinética , Cicloexenos/farmacologia , Efeito Citopatogênico Viral/efeitos dos fármacos , Cães , Farmacorresistência Viral , Estabilidade de Medicamentos , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/enzimologia , Vírus da Influenza A Subtipo H1N1/genética , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/enzimologia , Alphainfluenzavirus/enzimologia , Alphainfluenzavirus/genética , Betainfluenzavirus/enzimologia , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Mutação , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/farmacologia , Ácidos Fosforosos , Ligação Proteica , Ratos , Relação Estrutura-Atividade
20.
Org Lett ; 13(19): 5306-9, 2011 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-21913698

RESUMO

A feasible synthetic approach toward the Mycobacterium tuberculosis (Mtb) N-glycolyl lipid II-like molecule 1 is described. Compound 1 bears pendant undecaprenol and l-lysin moieties instead of the naturally occurring decaprenol and meso-diaminopimelic acid, which are not readily available. Functionalization of 1 with a fluorophore on the peptide side chain gave 14, which was found to be recognized as an Mtb TGase substrate. This result suggests it has tremendous utility for mechanistic studies, the characterization of mycobacterial enzymes, and mycobacterial TGase inhibitor evaluation.


Assuntos
Glicolipídeos/química , Glicolipídeos/metabolismo , Mycobacterium tuberculosis/metabolismo , Glicosiltransferases/metabolismo , Especificidade por Substrato
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