RESUMEN
The study presented here was conducted in order to gain a better understanding of the role of astroviruses (AsVs) in outbreaks of gastroenteritis among the elderly. This report is the first to provide detailed information on the molecular characteristics of an AsV causing an outbreak in an aged-care centre and is the first to clearly establish that individuals infected in such an outbreak were, in fact, elderly. The outbreak under investigation took place in Victoria, Australia, in October 2005. Twelve individuals (mean age +/- standard deviation [SD] 85.5 +/- 12.3 years) became ill during the outbreak from a total population of 86 susceptible residents. The mean duration (+/-SD) of illness was 2.3 +/- 1.6 days; symptoms included diarrhoea, abdominal pain, nausea and headache. No bacterial pathogens were detected. AsV was identified in five faecal specimens using electron microscopy and reverse transcription-polymerase chain reaction methodologies; no other gastroenteritis virus was detected. Nucleotide sequence analysis indicated the AsV identified could be assigned to the 1d lineage of AsV serotype 1 and that the AsV was not a recombinant form. The findings, taken together with previous work, indicate the AsV serotype most commonly associated with gastroenteritis outbreaks among the elderly is serotype 1 AsV.
Asunto(s)
Infecciones por Astroviridae/genética , Brotes de Enfermedades , Gastroenteritis/epidemiología , Gastroenteritis/virología , Hogares para Ancianos , Mamastrovirus/genética , Casas de Salud , Anciano de 80 o más Años , Australia/epidemiología , Heces/microbiología , Heces/virología , Femenino , Humanos , Control de Infecciones , Masculino , Mamastrovirus/clasificación , Mamastrovirus/patogenicidad , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , SerotipificaciónRESUMEN
The serine protease urokinase plasminogen activator (uPA) is thought to play a central role in tumor metastasis and angiogenesis. Molecular modeling studies suggest that 5-thiomethylthiopheneamidine inhibits uPA by binding at the S1 pocket of the active site. Further structure based elaboration of this residue resulted in a novel class of potent and selective inhibitors of uPA.
Asunto(s)
Antimetabolitos/farmacología , Tiofenos/farmacología , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidores , Antimetabolitos/síntesis química , Antimetabolitos/química , Sitios de Unión , Humanos , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Activador de Plasminógeno de Tipo Uroquinasa/fisiologíaRESUMEN
The serine protease urokinase (uPa) has been implicated in the progression of both breast and prostate cancer. Utilizing structure based design, the synthesis of a series of substituted 4-[2-amino-1,3-thiazolyl]-thiophene-2-carboxamidines is described. Further optimization of this series by substitution of the terminal amine yielded urokinase inhibitors with excellent activities.
Asunto(s)
Amidinas/síntesis química , Amidinas/farmacología , Activadores Plasminogénicos/antagonistas & inhibidores , Tiazoles/farmacología , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidores , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
Bicyclic thiazolidine lactam peptidomimetics 3-5 have been synthesized as potential analogues of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2 (PLG). Peptidomimetics 3 and 4 were designed to constrain two, psi 2 and phi 3, of the four torsion angles that define a beta-turn to values approximating those found for a type-II beta-turn, while 5 was designed as a compound that could not achieve a beta-turn conformation. Peptidomimetics 3 and 4 were found to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor, while 5 was found to be inactive. Like PLG the dose-response curves for 3 and 4 were bell-shaped in nature with the maximum effect occurring at a concentration of 1 microM. Both 3 and 4 were more effective than PLG in enhancing the binding of ADTN to dopamine receptors. The 5,5-bicyclic thiazolidine lactam peptidomimetic 3 enhanced the binding of ADTN by almost 200%, while the 6,5-bicyclic thiazolidine lactam peptidomimetic 4 enhanced the binding of ADTN by about 75%. These results provide further evidence in support of the hypothesis that the bioactive conformation of PLG is a type-II beta-turn.
Asunto(s)
Dopaminérgicos/metabolismo , Lactamas/síntesis química , Hormona Inhibidora de la Liberación de MSH/efectos de los fármacos , Péptidos/síntesis química , Receptores Dopaminérgicos/metabolismo , Tetrahidronaftalenos/metabolismo , Tiazoles/síntesis química , Animales , Bovinos , Lactamas/farmacología , Hormona Inhibidora de la Liberación de MSH/análogos & derivados , Péptidos/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
Hippocampal CA1 pyramidal cell neurons are sensitized over 30-fold to depolarization by L-2-amino-4-phosphonobutanoic acid (L-AP4) following exposure to L-quisqualic acid. This phenomenon has been termed the QUIS effect. In the present study several novel L-quisqualic acid analogues have been synthesized and tested for their interaction with the different components of the QUIS-effect system. Replacement of the oxadiazolidinedione ring of L-quisqualic acid with several other types of heterocyclic rings yielded the following quisqualic acid analogues: maleimide 2, N-methylmaleimide 3, N-(carboxymethyl)maleimide 4, succinimides 5A and 5B, and imidazolidinedione 6. None of these analogues were able to mimic the effects of L-quisqualic acid and sensitize hippocampal CA1 neurons to depolarization by L-AP4. Also, unlike L-serine O-sulfate, L-homocysteinesulfinic acid, or L-alpha-aminoadipic acid, none of the analogues were able to preblock or reverse the QUIS effect. However, when the IC50 values for inhibition of the CA1 synaptic field potential of analogues 2-6 were determined both before and after hippocampal slices were exposed to L-quisqualic acid, the IC50 values of analogues 3 and 4 were found to decrease more than 7-fold. Thus, these two compounds behave like L-AP4 rather than L-quisqualic acid in this system in that they exhibit increased potencies in slices that have been pretreated with L-quisqualic acid even though they cannot themselves induce this sensitization. Compounds 3 and 4, therefore, represent the first non-phosphorus-containing compounds to which hippocampal neurons become sensitized following exposure to L-quisqualic acid. No change in the IC50 values was observed for 5A or 5B. Analogues 2 and 6, on the other hand, displayed a high potency for inhibition of the evoked field potential even prior to treatment of the slices with L-quisqualic acid.
Asunto(s)
Hipocampo/efectos de los fármacos , Ácido Quiscuálico/análogos & derivados , Aminobutiratos/farmacología , Animales , Ciclización , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Electrofisiología , Potenciales Evocados/efectos de los fármacos , Hipocampo/fisiología , Imidazoles/síntesis química , Imidazoles/farmacología , Masculino , Maleimidas/química , Estructura Molecular , Ácido Quiscuálico/química , Ácido Quiscuálico/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Succinimidas/síntesis química , Succinimidas/farmacologíaRESUMEN
The following structural and conformationally constrained analogues of Ac-Asp-Glu-OH (1) were synthesized: Ac-Glu-Glu-OH (2), Ac-D-Asp-Glu-OH (3), Ac-Glu-Asp-OH (4), Ac-Asp-Asp-OH (5), Ac-Asp-3-aminohexanedioic acid (6), Ac-3-amino-3-(carboxymethyl)propanoyl-Glu-OH (7), N-succinyl-Glu-OH (8), N-maleyl-Glu-OH (9), N-fumaryl-Glu-OH (10), and Ac-delta ZAsp-Glu-OH (11). These analogues were evaluated for their ability to inhibit the hydrolysis of Ac-Asp-[3,4-3H]-Glu-OH by N-acetylated alpha-linked acidic dipeptidase (NAALA dipeptidase) in order to gain some insight into the structural requirements for the inhibition of this enzyme. Analogues 4-6 and 9 were very weak inhibitors of NAALA dipeptidase (Ki greater than 40 microM), while 2, 3, and 7 with Ki values ranging from 3.2-8.5 microM showed intermediate inhibitory activity. The most active inhibitors of NAALA dipeptidase were compounds 8, 10, and 11 with Ki values of 0.9, 0.4, and 1.4 microM, respectively. These results suggest that the relative spacing between the side chain carboxyl and the alpha-carboxyl group of the C-terminal residue may be important for binding to the active site of the enzyme. They also indicate that the chi 1 torsional angle for the aspartyl residue is in the vicinity of 0 degrees.