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At least 91 records · Page 5Linked to original sources
PubMed2006

Histamine H3 receptor antagonists: from target identification to drug leads.

The successful cloning and functional expression of the histamine H(3) receptor in the late 1990 s has greatly facilitated our efforts to identify small molecule, non-imidazole based compounds to permit the evaluation of H(3) antagonists in models of CNS disorders. High-throughput screening identified several series of lead compounds, including a series of imidazopyridines, which led to JNJ-6379490, a compound with high affinity for the human H(3) receptor. Analysis of structural features common to several series of non-imidazole H(3) receptor ligands resulted in a pharmacophore model. This model led to the design of JNJ-5207852, a diamine-based H(3) antagonist with good in vitro and in vivo efficacy but with an undesirable long half-life. However, further modifications of the template provided an understanding of the effect of structural modifications on pharmacokinetic properties, ultimately affording several additional series of compounds including JNJ-10181457, a compound with an improved pharmacokinetic profile. These compounds allowed in vivo pharmacological evaluation to show that H(3) antagonists promote wakefulness, but unlike modafinil and classical psychostimultants, they do not increase locomotor activity or produce any alteration of the EEG power spectral activity in rats. H(3) antagonists also increase extracellular acetylcholine and norepinephrine but not dopamine in rat frontal cortex and show efficacy in various models of learning-memory deficit. In addition, cFos immunoreactivity studies show H(3) antagonists activate neuronal cells in restricted rat brain regions in contrast to widespread activation after modafinil or amphetamine treatment. Therefore, H(3) antagonists are promising clinical candidates for the treatment of excessive day time sleepiness and/or cognitive disorders.

Animals↗
PubMed2006

Targeted identification of a unique glycan epitope of Schistosoma mansoni egg antigens using a diagnostic antibody.

The eggs of Schistosoma mansoni express a plethora of glycoconjugate antigens. A specific subset of these antigens can be detected in the serum or urine of infected individuals by a diagnostic sandwich ELISA using the anti-carbohydrate monoclonal antibody (mAb) 114-4D12-A [Nourel Din MS, Nibbeling R, Rotmans JP, Polderman AM, Krijger FW, Deelder AM. Quantitative determination of circulating soluble egg antigen in urine and serum of Schistosoma mansoni-infected individuals using a combined two-site enzyme-linked immunosorbent assay. Am J Trop Med Hyg 1994;50:585-94]. We used affinity chromatography to isolate the 114-4D12-binding glycoprotein subset from soluble egg antigens (SEA) of S. mansoni. SEA and the isolated SEA-subset (SEA-4D12) were subjected to reductive beta-elimination and hydrazinolysis to release intact glycans and glycan fragments, respectively, from the protein backbones. The released glycans were characterised by matrix-assisted laser-desorption-ionisation time-of-flight (MALDI-TOF) mass spectrometry (MS), liquid-chromatography (LC)-MS and gas chromatography (GC)-MS linkage analysis. Glycans released by reductive beta-elimination from SEA-4D12 were larger and more heavily fucosylated than glycans released from SEA. Most SEA-4D12 glycans contained a branched O-glycan core structure carrying up to 4 N-acetylhexosamines per chain which were substituted with maximum 12 fucose residues. Hydrazinolysis of SEA-4D12 resulted in the release of fucosylated antenna fragments. After 2-aminobenzamide (2AB)-labelling these fragments were subjected to 114-4D12-affinity purification. Normal phase (NP)-LC analysis of the flow-through and retained fractions indicated that the Fucalpha1-2Fucalpha1-3GalNAcbeta1-4(Fucalpha1-2Fucalpha1-3)GlcNAcbeta1- element forms the epitope of mAb 114-4D12. Most O-glycans from SEA-4D12 contain this structural element. Epitope-bearing N-glycans have not been found. In terms of abundance in total SEA, only a minority of all glycans possesses the epitope. This multifucosylated motif has so far only been found in schistosomes, providing a structural basis for the high specificity of the diagnostic antibody.

Animals↗
PubMed2002

Early auditory-visual interactions in human cortex during nonredundant target identification.

A common finding of behavioral studies is that objects characterized by redundant multisensory cues are identified more rapidly than the same objects presented in either unimodal condition. In a previous electrophysiological study in humans, we have described a network of crossmodal interactions that could be associated with this facilitation effect [M.H. Giard, F. Peronnet, J. Cogn. Neurosci. 11(5) (1999) 473-490]. Here, we sought to determine whether the recognition of objects characterized by nonredundant bimodal components may still induce crossmodal neural interactions. Subjects had to identify three objects defined either by auditory or visual features alone, or by the combination of nonredundant auditory and visual features. As expected, behavioral measures showed no sign of facilitation in bimodal processing. Yet, event-related potential analysis revealed the existence of early (<200 ms latency) crossmodal activities in sensory-specific and nonspecific cortical areas, that were partly dependent on the sensory dominance of the subjects to perform the task. Comparative analysis of the interaction patterns involved in redundant and nonredundant cue processing provides evidence for the robustness of the principle of crossmodal neural synergy that applies whatever the stimulus content (redundant or nonredundant information), and for the high flexibility of the neural networks of integration that are sensitive both to the nature of the perceptual task and to the sensory skill of the individual in that particular task.

Adult↗
PubMed1999

Targeted identification of markers linked to malaria and filarioid nematode parasite resistance genes in the mosquito Aedes aegypti.

Quantitative trait loci (QTL) have been identified for competence of the mosquito Aedes aegypti to transmit the avian malaria parasite Plasmodium gallinaceum and the human filarial parasite Brugia malayi. Efforts towards the map-based cloning of the associated genes are limited by the availability of genetic markers for fine-scale mapping of the QTL positions. Two F2 mosquito populations were subjected to bulked segregant analysis to identify random amplified polymorphic DNA (RAPD)-PCR fragments linked with the major QTL determining susceptibility to both parasites. Individual mosquitoes for the bulks were selected on the basis of their genotypes at restriction fragment length polymorphism (RFLP) loci tightly linked with the QTL. Pool-positive RAPD fragments were cloned and evaluated as RFLP markers. Of the 62 RAPD/RFLP fragments examined, 10 represented low-copy number sequences. Five of these clones were linked with the major QTL for P. gallinaceum susceptibility (pgs1), of which one clone mapped within the flanking markers that define the QTL interval. The remaining five clones were linked with the major QTL for B. malayi susceptibility (fsb1), and again one clone mapped within the flanking markers that define the QTL interval. In addition, nine RAPD/RFLP fragments were isolated that seem to be of non-mosquito origin.

Aedes↗
PubMed2006

The multifaceted circulating endothelial cell in cancer: towards marker and target identification.

Increases in the number of circulating endothelial cells (CECs) and progenitors (CEPs) have been reported in various pathological conditions including cancer. Preclinical studies have shown that CEC and CEP kinetics correlate well with several standard laboratory angiogenesis assays, which cannot be used in humans. At the clinical level, evidence is emerging that CEC kinetics and viability might correlate with clinical outcomes in cancer patients who undergo anti-angiogenic treatment. Therefore, CEC and CEP measurement has potential as a surrogate marker for monitoring anti-angiogenic treatment and drug activity, and could help to determine the optimal biological dose of anti-angiogenic drugs, which are being used with increasing frequency in medical oncology.

Angiogenesis Inhibitors↗
PubMed2003

Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors.

LAF389 is a synthetic analogue of bengamides, a class of marine natural products that produce inhibitory effects on tumor growth in vitro and in vivo. A proteomics-based approach has been used to identify signaling pathways affected by bengamides. LAF389 treatment of cells resulted in altered mobility of a subset of proteins on two-dimensional gel electrophoresis. Detailed analysis of one of the proteins, 14-3-3gamma, showed that bengamide treatment resulted in retention of the amino-terminal methionine, suggesting that bengamides directly or indirectly inhibited methionine aminopeptidases (MetAps). Both known MetAps are inhibited by LAF389. Short interfering RNA suppression of MetAp2 also altered amino-terminal processing of 14-3-3gamma. A high resolution structure of human MetAp2 co-crystallized with a bengamide shows that the compound binds in a manner that mimics peptide substrates. Additionally, the structure reveals that three key hydroxyl groups on the inhibitor coordinate the di-cobalt center in the enzyme active site.

14-3-3 Proteins↗
PubMed1998

Targeted identification of zinc finger genes expressed in rat lungs.

Control of alveolar cell growth and differentiation after pneumonectomy likely involves changes in expression of regulatory genes, including those encoding zinc finger (ZF) proteins. To explore this premise, total RNA from the lungs of control and pneumonectomized rats was reverse transcribed; PCRs were performed with degenerate primers corresponding to amino acid sequences HTGEKP and CPECGK(N), which are evolutionarily conserved among ZF genes. Reaction products corresponding to three and four ZF units were isolated and cloned. Sixteen clones were sequenced and found to represent rat lung ZF genes: six clones were highly similar or identical to known ZF genes and ten clones showed lower homology to known ZF genes and thus appear to represent new members of the ZF family. Northern analysis demonstrated differential expression of some ZF genes after pneumonectomy. Thus a PCR-based strategy with primers derived from evolutionarily conserved ZF protein sequences efficiently identifies ZF genes expressed in lung, some of which may play a role in cellular growth and differentiation.

Amino Acid Sequence↗