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101.
An estimated 2–3% of the world''s population is infected with hepatitis C virus (HCV), making it a major global health problem. Consequently, over the past 15 years, there has been a concerted effort to understand the pathophysiology of HCV infection and the molecular virology of replication, and to utilize this knowledge for the development of more effective treatments. The virally encoded non-structural serine protease (NS3) is required to process the HCV polyprotein and release the individual proteins that form the viral RNA replication machinery. Given its critical role in the replication of HCV, the NS3 protease has been recognized as a potential drug target for the development of selective HCV therapies. In this review, we describe the key scientific discoveries that led to the approval of boceprevir, a first-generation, selective, small molecule inhibitor of the NS3 protease. We highlight the early studies that reported the crystal structure of the NS3 protease, its role in the processing of the HCV polyprotein, and the structural requirements critical for substrate cleavage. We also consider the novel attributes of the NS3 protease-binding pocket that challenged development of small molecule inhibitors, and the studies that ultimately yielded milligram quantities of this enzyme in a soluble, tractable form suitable for inhibitor screening programs. Finally, we describe the discovery of boceprevir, from the early chemistry studies, through the development of high-throughput assays, to the phase III clinical development program that ultimately provided the basis for approval of this drug. This latest phase in the development of boceprevir represents the culmination of a major global effort to understand the pathophysiology of HCV and develop small molecule inhibitors for the NS3 protease. 相似文献
102.
病毒性脑膜炎、脑炎患儿的病原分析及部分生化指标变化的临床意义 总被引:2,自引:1,他引:1
目的:探讨病毒性脑膜炎、脑炎的病原及与部分生化指标改变的关系。方法:采用ELISA法进行血清抗体检测,终点法及速率法进行生化分析。结果:病毒性脑膜炎、脑炎患儿的病原分析:Ⅰ型副流感病毒(PIV)占24.5%,腺病毒(ADV)18.0%。柯萨奇B组病毒(CVB)占11.0%,呼吸道合胞病毒(RSV)占11.0%,乙脑病毒占9.0%,甲型流感病毒(IVA)占4.5%。小儿病毒性脑膜炎、脑炎的脑脊液(Cerebrospinal fluid,CSF)中,胆碱酯酶(CHE)的活性、总蛋白与磷(phosphor,P)的含量有显著改变(P<0.05),且CHE的活性与总蛋白、P的含量有相关性,钙(Ca)及镁(Mg)含量无显著改变(P>0.05)。结论:(1)在已知的几种致病病毒中,小儿病毒性脑膜炎、脑炎主要由PIV引起,其次是ADV、CVB、RSV。(2)小儿病毒性脑膜炎、脑炎的脑脊液中CHE的活性明显增高,提示小儿病毒性脑膜炎、脑炎将会影响胆碱能神经元的功能。(3)不同病毒对脑脊液CHE的活性影响不同,在已知的几种病毒中CVB对CHE的活性影响最大。 相似文献
103.
为探讨不同磁场处理水对淋巴细胞转化率的影响,采用交变磁场和静磁场处理水配制细胞培养液,与蒸馏水配制的细胞培养液进行比较。各种培养液均在相同条件下培养72h后离心并分离淋巴细胞,结果2种磁处理水能显著增强淋巴细胞转化率和提高细胞培养液中K~+、Na~+、Ca~(2+)、Cl~-、MMS、BUN、葡萄糖的含量(P<0.01),同时也能显著增强培养液中ALT、LDH的活性(P<0.01)。实验表明,磁处理水具有增强机体免疫功能和促进细胞物质能量代谢的作用。 相似文献
104.
Glutathione peroxidase activity in rat lens and other tissues in relation to dietary selenium intake 总被引:2,自引:0,他引:2
Glutathione peroxidase (E.C. 1.11.1.9: glutathione: H2O2 oxidoreductase) activity and selenium concentration were measured in lenses of female rats and their offspring after long-term feeding of either a selenium-supplemented () or selenium-deficient () diet. Long-term selenium deficiency decreased lens glutathione peroxidase activity in parent rats and their offspring to 15 and 14% respectively of supplemented controls. For comparison to lens, glutathione peroxidase was also measured in liver, heart, lung, erythrocytes, kidney, adrenal, testis, and brain of the offspring. Selenium deficiency caused the enzyme to decrease most dramatically in liver (to 0) and least in brain (to 62% of selenium supplemented controls). Although glutathione peroxidase in lens was lower than that in the other organs assayed, it was among the organs more sensitive to depletion caused by selenium deficiency. A short-term selenium deficiency of 8 weeks in newborn lambs had no effect on lens glutathione peroxidase, but the enzyme in organs such as liver was dramatically decreased. Therefore, an extensive period of selenium deficiency appears necessary to affect lens glutathione peroxidase activity, which probably relates to the relatively slow turnover and slow growth of the lens. The possible role of the seleno-enzyme, glutathione peroxidase, in the prevention of cataracts and the relationship of selenium to vitamin E and sulfur-containing amino acids in this regard are discussed. 相似文献
105.
The effect of orchidectomy in male rabbits and administration of testosterone to orchidectomized animals on the metabolism of glycosaminoglycans (GAG) has been studied. The response of the different GAG fractions in the aorta varies with the nature of the GAG, and in some cases is different in different segments of the aorta. Orchidectomy produced an increase in hyaluronic acid fraction, decrease in heparin sulphate fraction, and no response in the chondroitin sulphate A fraction in the aortic arch, thoracic aorta, and abdominal aorta. Chondroitin sulphate C and chondroitin sulphate B fractions decreased only in the abdominal aorta and were not significantly altered in the other two segments, while heparin fraction decreased only in the thoracic aorta and was not affected in the other segments. Administration of testosterone to the orchidectomized animals counteracted these changes in the aortic GAG fractions. The enzymes concerned with the synthesis of precursors of GAG—L-glutamine: D-fructose-6-phosphate aminotransferase, UDPG dehydrogenase, and UDPG pyrophosphorylase—all decreased in the orchidectomized animals; testosterone administration increased their activity in the orchidectomized animals. Enzymes concerned with degradation of GAG—β-glucuronidase, β-hexosaminidase, aryl sulphatase, cathepsin, and hyaluronidase—increased in the orchidectomized animals and decreased on administration of testosterone. Concentration of PAPS and activity of sulphate-activating system and sulphotransferase also decreased in the orchidectomized animals, and testosterone administration tended to restore this decrease to normal levels. 相似文献
106.
107.
Thue W. Schwartz Peter SaksØ Jens F. Rehfeld 《Clinica chimica acta; international journal of clinical chemistry》1978,89(3):381-386
The concentration and molecular form of gastrin in urine were determined radioimmunochemically. Urine from hypergastrinaemic patients (Zollinger-Ellison syndrome and pernicious anaemia) contained gastrins corresponding to the serum components I and II. The excretion of gastrin increased with increasing gastrin concentrations in serum. Urine from six subjects with normal concentrations of gastrin in serum contained "apparent" gastrin immunoreactivity which could not be removed by specific immunoabsorption. No gastrin was detectable by gel filtration of desalted and concentrated urine from normal subjects. The apparent immunoreactivity was due partly to interference by sodium chloride. The results indicate that hypergastrinaemic patients, in contrast to normal subjects, excrete gastrins in the urine. 相似文献
108.
109.
J.P. Flatt G.L. Blackburn G. Randers J.B. Stanbury 《Metabolism: clinical and experimental》1974,23(2):151-158
The hypoglycemic reaction following the injection of a large dose of insulin was studied in postabsorptive, anesthetized dogs. The rate of epinephrine release into the adrenal vein was monitored to provide an index of hypoglycemic stress at the level of the central nervous system. As expected an acute discharge of epinephrine was observed during the insulin-provoked hypoglycemia. It is shown that this epinephrine discharge can be prevented by infusing ketone bodies to sustain blood ketone body concentrations in the range of 1 to 2 mM. Arterial-venous differences across the head during hypoglycemia were of 0.20 ± 0.03 mmoles/liter for the extraction of ketone bodies. Since basal arterial-venous difference due to glucose oxidation were of 0.24 ± 0.11 mmoles/liter, it is concluded that the brain of the dog has the ability to use quantitatively important amounts of ketone bodies without prior adaptation to starvation. 相似文献
110.
A soluble cadmium-binding protein, with properties similar to metallothionein, has been isolated from rabbit alveolar macrophages. The macrophages were cultured in Medium 199 with Earle's salts for 24 hr in the presence of 10 μm CdCl2 and carrier-free 109Cd as a tracer. The isolation procedure began with application of a 100,000 g cell supernatant to a column of Sephadex G-75 Fine. The fraction containing the greatest amount of cadmium was eluted at a relative elution volume, , of 1.87. A molecular weight determination performed following Sephadex chromatography indicated that the apparent molecular weight of the impure protein was approximately 11,000. The fractions containing cadmium were pooled and purification procedures were applied, including acetone fractionation, DEAE-cellulose chromatography, and polyacrylamide gel electrophoresis. DEAE-Cellulose chromatography following acetone fractionation indicated the presence of two forms of metalloprotein as has been demonstrated previously in the isolation of cadmium-thionein from liver and kidney. The two forms of metalloprotein were subjected to polyacrylamide gel electrophoresis and, although separation was incomplete, bands obtained corresponded to those typically observed in rat liver. 相似文献