排序方式: 共有28条查询结果,搜索用时 191 毫秒
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David M. Wilson James Apps Nicholas Bailey Mark J. Bamford Isabel J. Beresford Michael A. Briggs Andrew R. Calver Barry Crook Robert P. Davis Susannah Davis David K. Dean Leanne Harris Tom D. Heightman Terry Panchal Christopher A. Parr Nigel Quashie Jon G.A. Steadman Joanne Schogger Andrew D. Medhurst 《Bioorganic & medicinal chemistry letters》2013,23(24):6897-6901
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties. 相似文献
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Functional characterization of both MAP kinases of the human malaria parasite Plasmodium falciparum by reverse genetics 总被引:2,自引:0,他引:2
Dorin-Semblat D Quashie N Halbert J Sicard A Doerig C Peat E Ranford-Cartwright L Doerig C 《Molecular microbiology》2007,65(5):1170-1180
The kinome of the human malaria parasite Plasmodium falciparum includes two genes encoding mitogen-activated protein kinase (MAPK) homologues, pfmap-1 and pfmap-2, but no clear orthologue of the MAPK kinase (MAPKK) family, raising the question of the mode of activation and function of the plasmodial MAPKs. Functional studies in the rodent malaria model Plasmodium berghei recently showed the map-2 gene to be dispensable for asexual growth and gametocytogenesis, but essential for male gametogenesis in the mosquito vector. Here, we demonstrate by using a reverse genetics approach that the map-2 gene is essential for completion of the asexual cycle of P. falciparum, an unexpected result in view of the non-essentiality of the orthologous gene for P. berghei erythrocytic schizogony. This validates Pfmap-2 as a potential target for chemotherapeutic intervention. In contrast, the other P. falciparum MAPK, Pfmap-1, is required neither for in vitro schizogony and gametocytogenesis in erythrocytes, nor for gametogenesis and sporogony in the mosquito vector. However, Pfmap-2 protein levels are elevated in pfmap-1(-) parasites, suggesting that Pfmap-1 fulfils an important function in asexual parasites that necessitates compensatory adaptation in parasites lacking this enzyme. 相似文献
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Gudin S Quashie NB Candlish D Al-Salabi MI Jarvis SM Ranford-Cartwright LC de Koning HP 《Experimental parasitology》2006,114(2):118-125
Purine uptake has been studied in many protozoan parasites in the last few years, and several of the purine transporters have been cloned. In contrast, very little is known about the salvage of preformed pyrimidines by protozoa, and no pyrimidine transporters have been cloned, yet chemotherapy based on pyrimidine nucleobases and nucleosides has been as effective as purine antimetabolites in the treatment of infectious and neoplastic disease. Here, we surveyed the presence of pyrimidine transporters in Trypanosoma brucei brucei. We could not detect any mediated uptake of thymine, thymidine or cytidine, but identified a very high-affinity transporter for cytosine, designated C1, with a K(m) value of 0.048+/-0.009 microM. We also confirmed the presence of the previously reported U1 uracil transporter and found it capable of mediating uridine uptake as well, with a K(m) of 33+/-5 microM. A higher-affinity U2 uridine transporter (K(m)=4.1+/-2.1 microM) was also identified, but efficiency of the C1 and U2-mediated transport was low. Pyrimidine antimetabolites were tested as potential trypanocidal agents and only 5-fluorouracil was found to be effective. This drug was efficiently taken up by bloodstream forms of T. b. brucei. 相似文献
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Replication slippage may cause parallel evolution in the secondary structures of mitochondrial transfer RNAs 总被引:9,自引:4,他引:5
Presence of the dihydrouridine (D) stem in the mitochondrial cysteine tRNA
is unusually variable among lepidosaurian reptiles. Phylogenetic and
comparative analyses of cysteine tRNA gene sequences identify eight
parallel losses of the D-stem, resulting in D-arm replacement loops.
Sampling within the monophyletic Acrodonta provides no evidence for
reversal. Slipped-strand mispairing of noncontiguous repeated sequences
during replication or direct replication slippage can explain repeats
observed within cysteine tRNAs that contain a D-arm replacement loop. These
two mechanisms involving replication slippage can account for the loss of
the cysteine tRNA D-stem in several lepidosaurian lineages, and may
represent general mechanisms by which the secondary structures of
mitochondrial tRNAs are altered.
相似文献
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The complete cDNA sequence and protein reading frame of a developmentally
regulated hemocyanin subunit in the Dungeness crab (Cancer magister) is
presented. The protein sequence is aligned with 18 potentially homologous
hemocyanin-type proteins displaying apparent sequence similarities.
Functional domains are identified, and a comparison of predicted
hydrophilicities, surface probabilities, and regional backbone
flexibilities provides evidence for a remarkable degree of structural
conservation among the proteins surveyed. Parsimony analysis of the protein
sequence alignment identifies four monophyletic groups on the arthropodan
branch of the hemocyanin gene tree: crustacean hemocyanins, insect
hexamerins, chelicerate hemocyanins, and arthropodan prophenoloxidases.
They form a monophyletic group relative to molluscan hemocyanins and
nonarthropodan tyrosinases. Arthropodan prophenoloxidases, although
functionally similar to tyrosinases, appear to belong to the arthropodan
hexamer- type hemolymph proteins as opposed to molluscan hemocyanins and
tyrosinases.
相似文献
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