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21.
NL Subasinghe E Khalil JM Travins F Ali SK Ballentine HR Hufnagel W Pan K Leonard RF Bone RM Soll CS Crysler N Ninan J Kirkpatrick MX Kolpak KA Diloreto SH Eisennagel ND Huebert CJ Molloy BE Tomczuk MD Gaul 《Bioorganic & medicinal chemistry letters》2012,22(16):5303-5307
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties. 相似文献
22.
Improving Keszthelyis simple model the evolutionary appearance of concentration difference of enanthiomeric compounds due to their differential decomposition by -rays is investigated taking into account the racemization as well. It is shown that if the difference in the cross sections is very small then the resulting concentration difference will never exceed the statistical fluctuations, while in the case of a sufficiently large difference in the cross sections the concentration difference can overgrow the statistical fluctuations in an evolutionary reasonable period of time. The relative difference of the concentrations, however, will be generally much smaller than that of the cross sections. Therefore some other, amplifying mechanism must be postulated in order to explain the optical purity of living beings. 相似文献
23.
Chilamakuri CS Reddy Sane Sudha Rani Bernard Offmann R Sowdhamini 《BMC research notes》2010,3(1):1-10
Background
Stem cell factor (SCF) receptor c-Kit is recognized as a key signaling molecule, which transduces signals for the proliferation, differentiation and survival of stem cells. Binding of SCF to its receptor triggers transactivation, leading to the recruitment of kinases and phosphatases to the docking platforms of c-Kit catalytic domain. Tyrosine phosphatase-1 (Shp-1) deactivates/attenuates 'Kit' kinase activity. Whereas, Asp816Val mutation in the Kit activation loop transforms kinase domain to a constitutively activated state (switch off-to-on state), in a ligand-independent manner. This phenomenon completely abrogates negative regulation of Shp-1. To predict the possible molecular basis of interaction between c-Kit and Shp-1, we have performed an in silico protein-protein docking study between crystal structure of activated c-Kit (phosphorylated c-Kit) and full length crystal structure of Shp-2, a close structural counterpart of Shp-1.Findings
Study revealed a stretch of conserved amino acids (Lys818 to Ser821) in the Kit activation domain, which makes decisive H-bonds with N-sh2 and phosphotyrosine binding pocket residues of the phosphatase. These H-bonds may impose an inhibitory steric hindrance to the catalytic domain of c-Kit, there by blocking further interaction of the activation loop molecules with incoming kinases. We have also predicted a phosphotyrosine binding pocket in SH2 domains of Shp-1, which is found to be predominantly closer to a catalytic groove like structure in c-Kit kinase domain.Conclusions
This study predicts that crucial hydrogen bonding between N-sh2 domain of Shp-1 and Kit activation loop can modulate the negative regulation of c-Kit kinase by Shp-1. Thus, this finding is expected to play a significant role in designing suitable gain-of-function c-Kit mutants for inducing conditional proliferation of hematopoietic stem cells. 相似文献24.
Unusual pattern of bacterial ice nucleation gene evolution 总被引:5,自引:0,他引:5
Edwards AR; Van den Bussche RA; Wichman HA; Orser CS 《Molecular biology and evolution》1994,11(6):911-920
Bacterial ice nucleation activity (INA+ phenotype) can be traced to the
product of a single gene, ina. A remarkably sparse distribution of this
phenotype within three bacterial genera indicates that the ina gene may
have followed an unusual evolutionary path. Southern blot analyses, coupled
with assays for ice-nucleating ability, revealed that within four bacterial
species an ina gene is present in some strains but absent from others.
Results of hybridization experiments using DNA fragments that flank the ina
gene suggested that the genotypic dimorphism of ina may be anomalous. A
phylogenetic analysis of 16S ribosomal RNA gene sequences from a total of
14 ina+ and ina- bacterial strains indicated that the ina+ bacteria are not
monophyletic but instead phylogenetically interspersed among ina- bacteria.
The relationships of ina+ bacteria inferred from ina sequence did not
coincide with those inferred from the 16S data. These results suggest the
possibility of horizontal transfer in the evolution of bacterial ina genes.
相似文献
25.
Studies on integrin alphaVbeta3 have implicated this receptor in a number of pathologies. In this article we describe some of our initial efforts to design small molecules alphaVbeta3 ligands incorporating an indole core template and an oxyguanidine as basic ending. Synthesis, biochemical activity and pharmacological properties are analyzed. 相似文献
26.
Lanter JC Markotan TP Zhang X Subasinghe N Kang FA Hou C Singer M Opas E McKenney S Crysler C Johnson D Molloy CJ Sui Z 《Bioorganic & medicinal chemistry letters》2011,21(24):7496-7501
As a result of further SAR studies on a piperidinyl piperidine scaffold, we report the discovery of compound 44, a potent, orally bioavailable CCR2 antagonist. While having some in vitro hERG activity, this molecule was clean in an in vivo model of QT prolongation. In addition, it showed excellent efficacy when dosed orally in a transgenic murine model of acute inflammation. 相似文献
27.
Wall MJ Chen J Meegalla S Ballentine SK Wilson KJ DesJarlais RL Schubert C Chaikin MA Crysler C Petrounia IP Donatelli RR Yurkow EJ Boczon L Mazzulla M Player MR Patch RJ Manthey CL Molloy C Tomczuk B Illig CR 《Bioorganic & medicinal chemistry letters》2008,18(6):2097-2102
A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model. 相似文献
28.
29.
Priscilla TY Law Siaw Shi Boon Chenghua Hu Raymond WM Lung Grace PY Cheung Wendy CS Ho Zigui Chen Paola Massimi Miranda Thomas David Pim Lawrence Banks Paul KS Chan 《Journal of cellular and molecular medicine》2019,23(2):1517-1527
Human papillomavirus 58 (HPV58) ranks the second or third in East Asian cervical cancers. Current studies on HPV58 are scarce and focus on the prototype. Previously, we identified the three most common circulating HPV58 E7 strains contained amino acid alterations: G41R/G63D (51%), T20I/G63S (22%) and T74A/D76E (14%) respectively. Among them, the T20I/G63S variant (V1) had a stronger epidemiological association with cervical cancer. We therefore suggested that V1 possessed stronger oncogenicity than the other two variants. Here, we performed phenotypic assays to characterize and compare their oncogenicities with HPV58 E7 prototype. Our results showed that overexpression of V1 conferred a higher colony‐forming ability to primary murine epithelial cells than prototype (P < 0.05) and other variants, implicating its higher immortalising potential. Further experiments showed that both V1 and prototype enhanced the anchorage‐independent growth of NIH/3T3 cells (P < 0.001), implicating their stronger transforming power than the two other variants. Moreover, they possessed an increased ability to degrade pRb (P < 0.001), which is a major effector pathway of E7‐driven oncogenesis. Our work represents the first study to compare the oncogenicities of HPV58 E7 prototype and variants. These findings deepened our understanding of HPV58 and might inform clinical screening and follow‐up strategy. 相似文献
30.
Sherin Antony Peeyush Kumar T Jobin Mathew TR Anju CS Paulose 《Journal of biomedical science》2010,17(1):7
Glucose homeostasis in humans is an important factor for the functioning of nervous system. Hypoglycemia and hyperglycemia is found to be associated with central and peripheral nerve system dysfunction. Changes in acetylcholine receptors have been implicated in the pathophysiology of many major diseases of the central nervous system (CNS). In the present study we showed the effects of insulin induced hypoglycemia and streptozotocin induced diabetes on the cerebellar cholinergic receptors, GLUT3 and muscle cholinergic activity. Results showed enhanced binding parameters and gene expression of Muscarinic M1, M3 receptor subtypes in cerebellum of diabetic (D) and hypoglycemic group (D + IIH and C + IIH). α7nAchR gene expression showed a significant upregulation in diabetic group and showed further upregulated expression in both D + IIH and C + IIH group. AchE expression significantly upregulated in hypoglycemic and diabetic group. ChAT showed downregulation and GLUT3 expression showed a significant upregulation in D + IIH and C + IIH and diabetic group. AchE activity enhanced in the muscle of hypoglycemic and diabetic rats. Our studies demonstrated a functional disturbance in the neuronal glucose transporter GLUT3 in the cerebellum during insulin induced hypoglycemia in diabetic rats. Altered expression of muscarinic M1, M3 and α7nAchR and increased muscle AchE activity in hypoglycemic rats in cerebellum is suggested to cause cognitive and motor dysfunction. Hypoglycemia induced changes in ChAT and AchE gene expression is suggested to cause impaired acetycholine metabolism in the cerebellum. Cerebellar dysfunction is associated with seizure generation, motor deficits and memory impairment. The results shows that cerebellar cholinergic neurotransmission is impaired during hyperglycemia and hypoglycemia and the hypoglycemia is causing more prominent imbalance in cholinergic neurotransmission which is suggested to be a cause of cerebellar dysfunction associated with hypoglycemia. 相似文献