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91.
Lamarre D Anderson PC Bailey M Beaulieu P Bolger G Bonneau P Bös M Cameron DR Cartier M Cordingley MG Faucher AM Goudreau N Kawai SH Kukolj G Lagacé L LaPlante SR Narjes H Poupart MA Rancourt J Sentjens RE St George R Simoneau B Steinmann G Thibeault D Tsantrizos YS Weldon SM Yong CL Llinàs-Brunet M 《Nature》2003,426(6963):186-189
Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics. 相似文献
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95.
Human mitochondrial tRNAs in health and disease 总被引:6,自引:0,他引:6
Florentz C Sohm B Tryoen-Tóth P Pütz J Sissler M 《Cellular and molecular life sciences : CMLS》2003,60(7):1356-1375
The human mitochondrial genome encodes 13 proteins, all subunits of the respiratory chain
complexes and thus involved in energy metabolism. These genes are translated by 22 transfer RNAs
(tRNAs), also encoded by the mitochondrial genome, which form the minimal set required for reading
all codons. Human mitochondrial tRNAs gained interest with the rapid discovery of correlations
between point mutations in their genes and various neuromuscular and neurodegenerative disorders.
In this review, emerging fundamental knowledge on the structure/function relationships of these
particular tRNAs and an overview of the large variety of mechanisms within translation, affected by
mutations, are summarized. Also, initial results on wide-ranging molecular consequences of mutations
outside the frame of mitochondrial translation are highlighted. While knowledge of mitochondrial
tRNAs in both health and disease increases, deciphering the intricate network of events leading
different genotypes to the variety of phenotypes requires further investigation using adapted
model systems.Received 3 December 2002; received after revision 14 January 2003; accepted 27 January 2003 相似文献
96.
Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis 总被引:12,自引:0,他引:12
Martinez LO Jacquet S Esteve JP Rolland C Cabezón E Champagne E Pineau T Georgeaud V Walker JE Tercé F Collet X Perret B Barbaras R 《Nature》2003,421(6918):75-79
The effect of high-density lipoprotein (HDL) in protecting against atherosclerosis is usually attributed to its role in 'reverse cholesterol transport'. In this process, HDL particles mediate the efflux and the transport of cholesterol from peripheral cells to the liver for further metabolism and bile excretion. Thus, cell-surface receptors for HDL on hepatocytes are chief partners in the regulation of cholesterol homeostasis. A high-affinity HDL receptor for apolipoprotein A-I (apoA-I) was previously identified on the surface of hepatocytes. Here we show that this receptor is identical to the beta-chain of ATP synthase, a principal protein complex of the mitochondrial inner membrane. Different experimental approaches confirm this ectopic localization of components of the ATP synthase complex and the presence of ATP hydrolase activity at the hepatocyte cell surface. Receptor stimulation by apoA-I triggers the endocytosis of holo-HDL particles (protein plus lipid) by a mechanism that depends strictly on the generation of ADP. We confirm this effect on endocytosis in perfused rat liver ex vivo by using a specific inhibitor of ATP synthase. Thus, membrane-bound ATP synthase has a previously unsuspected role in modulating the concentrations of extracellular ADP and is regulated by a principal plasma apolipoprotein. 相似文献
97.
Rapid degradation of a large fraction of newly synthesized proteins by proteasomes 总被引:47,自引:0,他引:47
MHC class I molecules function to present peptides eight to ten residues long to the immune system. These peptides originate primarily from a cytosolic pool of proteins through the actions of proteasomes, and are transported into the endoplasmic reticulum, where they assemble with nascent class I molecules. Most peptides are generated from proteins that are apparently metabolically stable. To explain this, we previously proposed that peptides arise from proteasomal degradation of defective ribosomal products (DRiPs). DRiPs are polypeptides that never attain native structure owing to errors in translation or post-translational processes necessary for proper protein folding. Here we show, first, that DRiPs constitute upwards of 30% of newly synthesized proteins as determined in a variety of cell types; second, that at least some DRiPs represent ubiquitinated proteins; and last, that ubiquitinated DRiPs are formed from human immunodeficiency virus Gag polyprotein, a long-lived viral protein that serves as a source of antigenic peptides. 相似文献
98.
Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor 总被引:26,自引:0,他引:26
HFE is related to major histocompatibility complex (MHC) class I proteins and is mutated in the iron-overload disease hereditary haemochromatosis. HFE binds to the transferrin receptor (TfR), a receptor by which cells acquire iron-loaded transferrin. The 2.8 A crystal structure of a complex between the extracellular portions of HFE and TfR shows two HFE molecules which grasp each side of a twofold symmetric TfR dimer. On a cell membrane containing both proteins, HFE would 'lie down' parallel to the membrane, such that the HFE helices that delineate the counterpart of the MHC peptide-binding groove make extensive contacts with helices in the TfR dimerization domain. The structures of TfR alone and complexed with HFE differ in their domain arrangement and dimer interfaces, providing a mechanism for communicating binding events between TfR chains. The HFE-TfR complex suggests a binding site for transferrin on TfR and sheds light upon the function of HFE in regulating iron homeostasis. 相似文献
99.
Volcanic uplift, caused by the accumulation of magma in subsurface reservoirs, is a common precursor to eruptions. But, for some volcanoes, uplift of metres or more has not yet led to an eruption. Here we present displacement maps of volcanoes in the Galápagos Islands, constructed using satellite radar interferometry, that might help explain this dichotomy. We show that all but one of the seven volcanoes on the islands of Isabela and Fernandina deformed during 1992-99. Cerro Azul and Fernandina erupted during the observation period and show evidence of inflation, co-eruptive deflation and shallow dyke intrusion. In contrast, the largest volcano, Sierra Negra, has not erupted, yet exhibits spatially and temporally variable deformation, with a maximum uplift of 2.7 m between 1992 and 1999, which can be modelled by a shallow inflating sill. Inflation during 1997-98, however, was accompanied by 'trapdoor' faulting on a steeply dipping fracture system within the caldera. Repeated trapdoor faulting over geological time has formed an arcuate intra-caldera ridge within Sierra Negra and may have acted to relax stresses above the magma chamber, inhibiting summit eruptions. Similar processes may help explain large uplift unaccompanied by eruptive activity at other volcanoes. 相似文献
100.
R. Marcos J. López de Sepúlveda N. Xamena A. Creus 《Cellular and molecular life sciences : CMLS》1981,37(6):559-560
Summary Ethidium bromide was fed toD. melanogaster andD. simulans males in order to test its toxic capacity and potency for the induction of dominant lethals. Our results show that ethidium bromide has a high toxicity and likewise produces dominant lethals to a significant extent in both species, but more effectively inD. melanogaster. 相似文献