Hit-to-lead optimization of a series of carboxamides of ethyl 2-amino-4-phenylthiazole-5-carboxylates as novel adenosine A2A receptor antagonists

Herein we describe the discovery of a series of novel adenosine A_2A receptor antagonists. A successful hit-to-lead optimization of an HTS hit led to replacement of a metabolically labile ester moiety with a heteroaromatic group. A compound from the series, (cyclopropanecarboxylic acid [5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-yl]-amide, compound 13), was shown to be effective in reversing haloperidol-induced hypolocomotion, a model of motor dysfunction in Parkinson’s Disease.     

Identification of proteins related to the stress response in <Emphasis Type="Italic">Enterococcus faecalis</Emphasis> V583 caused by bovine bile

Background  

Enterococcus faecalis is an opportunistic pathogen and one of the most important causes of hospital infections. Bile acids are a major stress factor bacteria have to cope with in order to colonize and survive in the gastro-intestinal tract. The aim of this study was to investigate the effects of bile acids on the intracellular proteome of E. faecalis V583.     

Controlling electron transfer in Acyl-CoA oxidases and dehydrogenases: a structural view

Plants produce a unique peroxisomal short chain-specific acyl-CoA oxidase (ACX4) for beta-oxidation of lipids. The short chain-specific oxidase has little resemblance to other peroxisomal acyl-CoA oxidases but has an approximately 30% sequence identity to mitochondrial acyl-CoA dehydrogenases. Two biochemical features have been linked to structural properties by comparing the structures of short chain-specific Arabidopsis thaliana ACX4 with and without a substrate analogue bound in the active site to known acyl-CoA oxidases and dehydrogenase structures: (i) a solvent-accessible acyl binding pocket is not required for oxygen reactivity, and (ii) the oligomeric state plays a role in substrate pocket architecture but is not linked to oxygen reactivity. The structures indicate that the acyl-CoA oxidases may encapsulate the electrons for transfer to molecular oxygen by blocking the dehydrogenase substrate interaction site with structural extensions. A small binding pocket observed adjoining the flavin adenine dinucleotide N5 and C4a atoms could increase the number of productive encounters between flavin adenine dinucleotide and O2.     

Paneling human thyroid cancer cell lines for candidate proteins for targeted anti-angiogenic therapy

Tumor angiogenesis is believed to result from an imbalance of pro- and anti-angiogenic factors, some of which are candidates for targeted therapy. Such therapy has raised hopes for patients with undifferentiated thyroid carcinomas, who are facing a grave prognosis with a survival of only months. In this study, in vivo growth of xenografted human thyroid carcinomas unexpectedly responded quite differently to neutralizing anti-vascular endothelial growth factor (VEGF) antibody. In particular, lasting inhibition as well as accelerated growth occurred after treatment. Consequently, a panel of anti-angiogenic factors was addressed in a representative sample of thyroid carcinoma lines. VEGF, fibroblast growth factor (FGF-2), and endostatin were demonstrated by Western blotting and EIA, whereas PDGF-A, PDGF-B, and IL-6 were negative. Quantification of VEGF, FGF-2, and endostatin revealed a wide range of concentrations from 500 to 4,200 pg/ml VEGF, 5 to 60 pg/ml FGF-2, and 50 to 300 pg/ml endostatin, not related to a particular histologic thyroid carcinoma background. Angiostatin (kringles 1-3) was detected in all, but one of the cell lines. Finally, aaATIII was confirmed in FTC133 cells. These data highlight the complex regulation of angiogenesis in thyroid carcinoma cell lines and suggest that the array of angiogenic factors differs markedly between individual cell lines. For the first time, angiostatin, endostatin, and possibly also aaATIII are identified as novel candidate regulators of angiogenesis in thyroid carcinoma cells.     

Comorbidity among HHT patients and their controls in a 20 years follow-up period

Background

Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disorder with a wide variety of clinical manifestations due to the presence of multiple arteriovenous malformations in various tissues and organs.

Objective

To study the need for hospital admittance in a group of HHT patients and matched controls during a 20?years follow-up period commencing in 1995.

Methods

All HHT patients in the County of Funen, Denmark, were included. For each patient, three age and sex matched controls were identified at the time of enrolment. Data on all hospitalisations were extracted from the national health registers and compared with clinical records. The hospitalisations were grouped as HHT relevant or not HHT relevant based on the discharge diagnosis (International Classification of Diseases, ICD10) and with particular focus on infections, bleedings and thromboembolic events.Patients with HHT were compared with controls concerning the first time incidence of each discharge diagnosis.

Results

We included 73 HHT patients and 219 controls of which one control was lost to follow-up. HHT-patients had significantly more hospitalisations per person caused by infections in joints and bones, but not caused by infections in general. Bleeding episodes were, as expected, more frequent among the HHT-patients. The study revealed a similar incidence of abscesses and thromboembolisms, including in the central nervous system, among the HHT patients and controls.

Conclusions

Based on this study Danish HHT patients had an increased comorbidity of infections in joints and bones and of bleeding episodes. However, the incidence of thromboembolisms, cerebral abscesses and other conditions commonly considered related to HHT was comparable between the patients and the controls. The patients included in this study were closely monitored at a highly specialised HHT Centre where they received relevant diagnostic evaluation, treatment and counselling. Since this is assumed to benefit the overall health of the patients, it may explain why these patients were less prone to comorbidity than other studies have suggested.

     

HLA-Specific Intracellular Epitope Processing Shapes an Immunodominance Pattern for HLA-B*57 That Is Distinct from HLA-B*58:01

HLA-B*57 is strongly associated with immune control of HIV and delayed AIDS progression. The closely related, but less protective, HLA-B*58:01 presents similar epitopes, but HLA-B*58:01⁺ individuals do not generate CD8⁺ T cells targeting the KF11-Gag epitope, which has been linked to low viremia. Here we show that HLA-B*58:01 binds and presents KF11 peptide, but HIV-infected HLA-B*58:01⁺ cells fail to process KF11. This unexpected finding demonstrates that immunodominance patterns can be influenced by intracellular events independent of HLA binding motifs.