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1.
Parasite Immunol ; 46(2): e13026, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38372616

RESUMO

ES-62, a protein secreted by Acanthocheilonema viteae, is anti-inflammatory by virtue of covalently attached phosphorylcholine (PC) residues and thus a library of drug-like small molecule analogues (SMAs) based on its PC moieties has been designed for therapeutic purposes. Two members, SMAs 11a and 12b, were previously found to suppress production of pro-inflammatory cytokines by mouse bone marrow-derived macrophages (BMMs) exposed to cytosine-phosphate-guanosine oligodeoxynucleotides (CpG), agonists for Toll-like receptor 9. In order to explore the mechanism of action underlying such activities, an untargeted mass spectrometry-based metabolomics screen was undertaken. Stimulation of BMMs with CpG produced significant metabolic changes relating to glycolysis and the TCA cycle but the SMAs had little impact on this. Also, the SMAs did not promote alterations in metabolites known to be associated with macrophage M1/M2 polarization. Rather, BMMs exposed to SMAs 11a or 12b prior to CpG treatment, or even alone, revealed downregulation of metabolites of creatine, a molecule whose major role is in the transport of high energy phosphate from the mitochondria to the cytosol. These data therefore provide insight into a possible mechanism of action of molecules with significant therapeutic potential that has not previously been described for parasitic worm products.


Assuntos
Creatina , Helmintos , Animais , Camundongos , Macrófagos , Anti-Inflamatórios , Fosfatos
3.
Parasite Immunol ; 38(6): 340-51, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27059010

RESUMO

ES-62 is a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that protects against ovalbumin (OVA)-induced airway hyper-responsiveness in mice by virtue of covalently attached anti-inflammatory phosphorylcholine (PC) residues. We have recently generated a library of small molecule analogues (SMAs) of ES-62 based around its active PC moiety as a starting point in novel drug development for asthma and identified two compounds - termed 11a and 12b - that mirror ES-62's protective effects. In this study, we have moved away from OVA, a model allergen, to test the SMAs against two clinically relevant allergens - house dust mite (HDM) and cockroach allergen (CR) extract. We show that both SMAs offer some protection against development of lung allergic responses to CR, in particular reducing eosinophil infiltration, whereas only SMA 12b is effective in protecting against eosinophil-dependent HDM-induced allergy. These data therefore suggest that helminth molecule-induced protection against model allergens may not necessarily translate to clinically relevant allergens. Nevertheless, in this study, we have managed to demonstrate that it is possible to produce synthetic drug-like molecules based on a parasitic worm product that show therapeutic potential with respect to asthma resulting from known triggers in humans.


Assuntos
Acanthocheilonema/química , Alérgenos/imunologia , Proteínas de Helminto/imunologia , Fatores Imunológicos/imunologia , Hipersensibilidade Respiratória/prevenção & controle , Acanthocheilonema/imunologia , Animais , Baratas/química , Baratas/imunologia , Feminino , Proteínas de Helminto/administração & dosagem , Proteínas de Helminto/genética , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/genética , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pyroglyphidae/química , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/imunologia
4.
Sci Rep ; 6: 19224, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26763929

RESUMO

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma.


Assuntos
Antiasmáticos/farmacologia , Asma/imunologia , Proteínas de Helminto/farmacologia , Fatores Imunológicos/farmacologia , Remodelação das Vias Aéreas , Alérgenos/imunologia , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Asma/patologia , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo
5.
Lupus ; 24(13): 1437-42, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26085597

RESUMO

INTRODUCTION: ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage. METHODS: SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria. RESULTS: SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition. CONCLUSIONS: SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate.


Assuntos
Proteínas de Helminto/farmacologia , Camundongos Endogâmicos MRL lpr , Adjuvantes Imunológicos/farmacologia , Animais , Anticorpos Antinucleares/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fatores Imunológicos , Interleucina-6/metabolismo , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Nefrite/tratamento farmacológico , Nefrite/patologia , Proteinúria/tratamento farmacológico , Proteinúria/patologia
6.
J Med Chem ; 43(17): 3257-66, 2000 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-10966744

RESUMO

Four new ligands that bind to the minor groove of DNA have been designed, synthesized, and evaluated by DNA footprinting. Two of the ligands are polyamides containing central regions with five or six N-methylpyrrole units, conferring hydrophobicity and good binding affinity but without retaining the correct spacing for hydrogen bonding in the base of the minor groove. The two remaining ligands have central regions which are head-to-head-linked polyamides, in which the linker is designed to improve the phasing of hydrogen bonding of the ligand with the floor of the minor groove. The highest affinity was obtained with the two polypyrroles without headgroup spacers, indicating that H-bond phasing is secondary in determining affinity compared to the major hydrophobic driving force. With a dimethylaminoalkyl group, representing a moiety with modest base strength, at both ends, water solubility is good and pH-partition theory predicts that penetration through lipid membranes will be enhanced, compared to strongly basic amidine analogues of the alkaloid precursors. All four compounds bind to DNA, with strong selectivity for AT sequences but some tolerance of GC base pairs and subtle individual preferences. The data show that very high affinities can be anticipated for future compounds in this series, but drug design must take account of overall physicochemical properties as well as the details of hydrogen bonding between ligands and the floor of the minor groove.


Assuntos
DNA/química , Netropsina/análogos & derivados , Pirróis/química , DNA/síntese química , Pegada de DNA , Eletroforese em Gel de Poliacrilamida , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Ligantes , Netropsina/síntese química , Netropsina/química , Pirróis/síntese química , Solubilidade
7.
Acta Crystallogr C ; 56(Pt 6): E265-6, 2000 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15263122

RESUMO

The title compound, C(10)H(10)O(5), was found to exist as the endo-cis isomer with a pair of enantiomers in the asymmetric unit. The cyclohexene ring is folded about the methylene-to-CH(acetoxy) vector to give a boat conformation.

8.
Chem Phys Lipids ; 83(1): 45-59, 1996 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-8858832

RESUMO

A series of novel sterols was synthesised as probes for the enzymatic and cellular functions of two important enzymes of intracellular cholesterol metabolism, acyl-CoA:cholesterol acyltransferase (ACAT) and cholesterol 7 alpha-hydroxylase. The compounds were 6-fluoro-5-cholesten-3 beta-ol (6-fluorocholesterol), 7-cholesten-3 beta-ol (7-cholestenol), 6 beta-fluorocholestan-3 beta-ol (6 beta-fluorocholestanol), 3-acetoxy-6-fluorocholestan-3 beta-ol (3-acetoxy-6-fluorocholestanol) and 7-methoxy-5-cholesten-3 beta-ol (7-methoxycholesterol). They were designed to reveal the effect of small changes in sterol structure, particularly reactivity of certain parts of the ring structure and polarity, on enzyme activity and intracellular cholesterol metabolism. The 3 beta-hydroxy group was essential for interaction with both enzymes since 3-acetoxy-6-fluorocholestanol did not affect any of the enzyme-catalysed reactions. 6-Fluorocholesterol and 7-cholestenol had no effect on cholesterol esterification but did inhibit the hydroxylation of cholesterol, as did the other compounds with groups that could influence the 7 position, namely 6 beta-fluorocholestanol and 7-methoxycholesterol. The fluorocholestanols were all competitive substrates for cholesterol esterification in cell-free and cellular assays of ACAT activity. 7-Methoxycholesterol was a surprisingly effective inhibitor of ACAT for a simple sterol. However, 6-fluorocholesterol did not have any effect on ACAT, suggesting that interactions between the enzyme and the region around C-6 and C-7 of the sterol are important. These results show that it is possible to dissect components of cholesterol metabolism using simple, specifically substituted sterols and thus define a new approach to studying the relationships between the various enzymes that catalyse intracellular cholesterol metabolism.


Assuntos
Colesterol/metabolismo , Esteróis/farmacologia , Animais , Células CACO-2 , Sistema Livre de Células , Colesterol 7-alfa-Hidroxilase/metabolismo , Ésteres do Colesterol/metabolismo , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Sondas Moleculares/síntese química , Sondas Moleculares/química , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Esterol O-Aciltransferase/metabolismo , Esteróis/síntese química , Esteróis/química , Relação Estrutura-Atividade
11.
Toxicon ; 31(10): 1293-303, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8303723

RESUMO

Cobra venoms (Naja species) contain a little-understood peptidase activity which shows specificity towards small peptides containing glycine and non-polar aromatic/aliphatic residues. We have examined the ability of whole cobra venom to degrade several types of peptide with emphasis on the action of Taiwan cobra (Naja naja atra) venom on L-alanylglycylglycine and glycylglycyl-L-phenylalanine. These are competing substrates, and it proved possible to generate inhibitors of the degradation of glycylglycyl-L-phenylalanine by synthesizing L-alanylglycylglycine analogues in which the peptide bond between the second and third residues had been replaced by different linkages. These analogues were themselves resistant to hydrolysis. The peptidase activity can also be inhibited by bestatin, captopril and chloromethyl ketones. Kinetic analyses suggested that even the best substrate discovered was of poor efficacy, so the natural peptide substrate remains to be identified. In unsuccessful attempts to devise a reliable chromogenic assay, it was found that the venom had activity against N-blocked amino acid p-nitrophenol esters, but not against leucine p-nitroanilide or ester substrates for trypsin-like and chymotrypsin-like enzymes.


Assuntos
Aminopeptidases/metabolismo , Venenos Elapídicos/enzimologia , Sequência de Aminoácidos , Aminopeptidases/antagonistas & inibidores , Aminopeptidases/isolamento & purificação , Animais , Cromatografia Líquida de Alta Pressão , Dados de Sequência Molecular , Espectrofotometria , Especificidade por Substrato
14.
Biotechnol Bioeng ; 38(10): 1137-43, 1991 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-18600708

RESUMO

Porcine pancreatic lipase immobilized on celite particles has been employed as a catalyst for the esterification of dodecanol and decanoic acid in a predominantly organic system. Solvent influence on the equilibrium position and on the catalyst activity has been studied using 20 solvents, including aliphatic and aromatic hydrocarbons, ethers, ketones, nitro- and halogenated hydrocarbons, and esters. The equilibrium constant for esterification correlates well with the solubility of water in the organic solvent, which in turn shows a good relationship with a function of Guttman's donor number and the electron pair acceptance index number of the solvent. This may be rationalized in terms of the requirements for solvation of water and of the reactants. The catalyst activity, measured as the initial rate of the esterification reaction, is best correlated as a function of both n-octanol-water partition coefficient (log P) and either the electron pair acceptance index or the polarizability.

15.
Experientia ; 47(11-12): 1139-1148, 1991 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-1765126

RESUMO

Molecular recognition impinges upon many fields of biological chemistry, especially those involving catalytic processes. This review gives examples from studies at Strathclyde of both small and macromolecular systems. Mechanism-based enzyme inhibitors are described with reference to dihydrofolate reductase, dihydroorotate dehydrogenase, and cholesterol metabolism. Applications of molecular recognition related to synthetic transformations are discussed in terms of aromatic substitution, chemically modified papain, and catalytic antibodies for Diels-Alder reactions.


Assuntos
Inibidores Enzimáticos/química , Enzimas/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Animais , Anticorpos/química , Catálise , Di-Hidro-Orotato Desidrogenase , Desenho de Fármacos , Antagonistas do Ácido Fólico , Humanos , Oxirredutases/antagonistas & inibidores , Esteroide Hidroxilases/antagonistas & inibidores , Esteroides/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato
16.
Sci Prog ; 75(298 Pt 3-4): 323-59, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1842854

RESUMO

The increased understanding of biological phenomena on a molecular level has made it possible to develop powerful approaches to the discovery of new drugs. Once a molecular hypothesis can be derived from the biochemistry, pharmacology, or physiology of the disease, a chemical strategy can be evolved to identify compounds that will serve as leads to new drugs. Several approaches are available and may be used individually or combined to solve a problem. Ideas can be generated from the structures of known biologically active compounds, from mechanistic studies of reactions catalysed by enzymes, or from molecular modelling of intermolecular interactions using advanced computer technology. All of these approaches require substantial inputs from organic (principally synthetic), physical, and theoretical chemists together with the biological contribution in the assay and evaluation of compounds. This article outlines some of the principles involved in the search for new drugs today discovery from the chemical point of view and illustrates the discussion with many examples of commercial drugs and compounds currently under development.


Assuntos
Química Farmacêutica , Composição de Medicamentos/métodos , Desenho de Fármacos , Humanos
17.
Ciba Found Symp ; 159: 201-8; discussion 208-10, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1959448

RESUMO

Catalytic antibodies have created a new dimension in protein chemistry. In these studies it is particularly valuable to investigate systems for which natural enzymic catalysts are unknown. At Strathclyde we have examined several ways of preparing homochiral building blocks for organic synthesis. Antibodies that catalyse the Diels-Alder reaction have been characterized. The target reaction was the addition of acetoxybutadiene to N-substituted maleimides, a reaction that should give a pentafunctional homochiral building block. Catalytic antibodies can give insight into the mechanism of catalysis by proteins. We have investigated an adventitious hydrolytic antibody that cleaves activated esters. We have also shown that an antibody raised to ampicillin for analytical purposes catalyses hydrolysis of the beta-lactam ring.


Assuntos
Anticorpos/metabolismo , Proteínas/química , Animais , Formação de Anticorpos/fisiologia , Catálise , Hidrólise , Estrutura Molecular
19.
Biochim Biophys Acta ; 1002(3): 401-4, 1989 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-2713389

RESUMO

The effects of 6,6-difluorocholestanol and 7,7-difluorocholestanol on enzymes of hepatic liver cholesterol were examined. Neither compound affected the activity of 3-hydroxy-3-methylglutaryl-CoA reductase. 7,7-Diffluorocholestanol had no effect on the activity of acyl-CoA: cholesterol acyltransferase or cholesterol 7 alpha-hydroxylase. However, 6,6-difluorocholestanol was a competitive substrate for cholesterol in the esterification of cholesterol catalysed by the acyltransferase. 6,6-Difluorocholestanol also inhibited hydroxylation of cholesterol by cholesterol 7 alpha-hydroxylase but was not itself a substrate for this enzyme. These results show that substitutents in ring B of the sterol can have a significant effect on the binding of the sterol to enzymes and to the catalytic mechanism if the substituent is close to the groups in the molecule that participate.


Assuntos
Colestanóis/farmacologia , Colesterol/metabolismo , Inibidores Enzimáticos/farmacologia , Microssomos Hepáticos/enzimologia , Animais , Ligação Competitiva , Hidroximetilglutaril-CoA Redutases/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Esterol O-Aciltransferase/metabolismo
20.
Clin Chim Acta ; 175(3): 285-9, 1988 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-2843310

RESUMO

1H spin echo NMR of the leukemic cell line J-lll is reported. Phosphorylcholine, phosphorylcreatine, lactate and mobile triglyceride are identified as constituents of the cytosolic pool in the intact and viable cells. The concentration of cells in the NMR tube is high (approx. 10(9) in 0.4 ml) and as a result the available oxygen is restricted, making the NMR experiment a plausible in vitro tumour model in which kinetics in the living cell can be probed in a non-invasive manner. Treatment with pharmacological concentrations of the drug doxorubicin produced immediate enhanced anaerobic glycolysis and eventual cell death.


Assuntos
Doxorrubicina/farmacologia , Glicólise/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Lactatos/metabolismo , Leucemia/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Prótons
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