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211.
Clive A. Slaughter 《Journal of biomolecular techniques》2015,26(3):113-117
This column highlights recently published articles that are of interest to the readership of this publication. We encourage ABRF members to forward information on articles they feel are important and useful to Clive Slaughter, Georgia Regents University-University of Georgia Medical Partnership, 1425 Prince Ave., Athens, GA 30606, USA. Phone: 706-713-2216; Fax: 706-713-2221; E-mail: ude.agu@thgualsc; or to any member of the Editorial Board. Article summaries reflect the reviewer’s opinions and not necessarily those of the association. 相似文献
212.
Lei Feng Amit Sharma Alison Slaughter Nivedita Jena Yasuhiro Koh Nikolozi Shkriabai Ross C. Larue Pratiq A. Patel Hiroaki Mitsuya Jacques J. Kessl Alan Engelman James R. Fuchs Mamuka Kvaratskhelia 《The Journal of biological chemistry》2013,288(22):15813-15820
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a very promising new class of anti-HIV-1 agents that exhibit a multimodal mechanism of action by allosterically modulating IN multimerization and interfering with IN-lens epithelium-derived growth factor (LEDGF)/p75 binding. Selection of viral strains under ALLINI pressure has revealed an A128T substitution in HIV-1 IN as a primary mechanism of resistance. Here, we elucidated the structural and mechanistic basis for this resistance. The A128T substitution did not affect the hydrogen bonding between ALLINI and IN that mimics the IN-LEDGF/p75 interaction but instead altered the positioning of the inhibitor at the IN dimer interface. Consequently, the A128T substitution had only a minor effect on the ALLINI IC50 values for IN-LEDGF/p75 binding. Instead, ALLINIs markedly altered the multimerization of IN by promoting aberrant higher order WT (but not A128T) IN oligomers. Accordingly, WT IN catalytic activities and HIV-1 replication were potently inhibited by ALLINIs, whereas the A128T substitution in IN resulted in significant resistance to the inhibitors both in vitro and in cell culture assays. The differential multimerization of WT and A128T INs induced by ALLINIs correlated with the differences in infectivity of HIV-1 progeny virions. We conclude that ALLINIs primarily target IN multimerization rather than IN-LEDGF/p75 binding. Our findings provide the structural foundations for developing improved ALLINIs with increased potency and decreased potential to select for drug resistance. 相似文献
213.
214.
Garbaccio RM Fraley ME Tasber ES Olson CM Hoffman WF Arrington KL Torrent M Buser CA Walsh ES Hamilton K Schaber MD Fernandes C Lobell RB Tao W South VJ Yan Y Kuo LC Prueksaritanont T Slaughter DE Shu C Heimbrook DC Kohl NE Huber HE Hartman GD 《Bioorganic & medicinal chemistry letters》2006,16(7):1780-1783
2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy. 相似文献
215.
Cox CD Torrent M Breslin MJ Mariano BJ Whitman DB Coleman PJ Buser CA Walsh ES Hamilton K Schaber MD Lobell RB Tao W South VJ Kohl NE Yan Y Kuo LC Prueksaritanont T Slaughter DE Li C Mahan E Lu B Hartman GD 《Bioorganic & medicinal chemistry letters》2006,16(12):3175-3179
Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound. 相似文献
216.
Joubert DA Slaughter AR Kemp G Becker JV Krooshof GH Bergmann C Benen J Pretorius IS Vivier MA 《Transgenic research》2006,15(6):687-702
Polygalacturonase-inhibiting proteins (PGIPs) selectively inhibit polygalacturonases (PGs) secreted by invading plant pathogenic fungi. PGIPs display differential inhibition towards PGs from different fungi, also towards different isoforms of PGs originating from a specific pathogen. Recently, a PGIP-encoding gene from Vitis vinifera (Vvpgip1) was isolated and characterised. PGIP purified from grapevine was shown to inhibit crude polygalacturonase extracts from Botrytis cinerea, but this inhibitory activity has not yet been linked conclusively to the activity of the Vvpgip1 gene product. Here we use a transgenic over-expression approach to show that the PGIP encoded by the Vvpgip1 gene is active against PGs of B. cinerea and that over-expression of this gene in transgenic tobacco confers a reduced susceptibility to infection by this pathogen. A calculated reduction in disease susceptibility of 47–69% was observed for a homogeneous group of transgenic lines that was statistically clearly separated from untransformed control plants following infection with Botrytis over a 15-day-period. VvPGIP1 was subsequently purified from transgenic tobacco and used to study the specific inhibition profile of individual PGs from Botrytis and Aspergillus. The heterologously expressed and purified VvPGIP1 selectively inhibited PGs from both A. niger and B.␣cinerea, including BcPG1, a PG from B. cinerea that has previously been shown to be essential for virulence and symptom development. Altogether our data confirm the antifungal nature of the VvPGIP1, and the in vitro inhibition data suggest at least in part, that the VvPGIP1 contributed to the observed reduction in disease symptoms by inhibiting the macerating action of certain Botrytis PGs in planta. The ability to correlate inhibition profiles to individual PGs provides a more comprehensive analysis of PGIPs as antifungal genes with biotechnological potential, and adds to our understanding of the importance of PGIP:PG interactions during disease and symptom development in plants.Dirk A. Joubert and Ana R. Slaughter contributed equally to this work. 相似文献
217.
Diluk RW Kannangara Sheena N Ramasamy Praveen L Indraratna Sophie L Stocker Garry G Graham Graham Jones Ian Portek Kenneth M Williams Richard O Day 《Arthritis research & therapy》2012,14(4):R189
Introduction
Hyperuricemia is the greatest risk factor for gout and is caused by an overproduction and/or inefficient renal clearance of urate. The fractional renal clearance of urate (FCU, renal clearance of urate/renal clearance of creatinine) has been proposed as a tool to identify subjects who manifest inefficient clearance of urate. The aim of the present studies was to validate the measurement of FCU by using spot-urine samples as a reliable indicator of the efficiency of the kidney to remove urate and to explore its distribution in healthy subjects and gouty patients.Methods
Timed (spot, 2-hour, 4-hour, 6-hour, 12-hour, and 24-hour) urine collections were used to derive FCU in 12 healthy subjects. FCUs from spot-urine samples were then determined in 13 healthy subjects twice a day, repeated on 3 nonconsecutive days. The effect of allopurinol, probenecid, and the combination on FCU was explored in 11 healthy subjects. FCU was determined in 36 patients with gout being treated with allopurinol. The distribution of FCU was examined in 118 healthy subjects and compared with that from the 36 patients with gout.Results
No substantive or statistically significant differences were observed between the FCUs derived from spot and 24-hour urine collections. Coefficients of variation (CVs) were both 28%. No significant variation in the spot FCU was obtained either within or between days, with mean intrasubject CV of 16.4%. FCU increased with probenecid (P < 0.05), whereas allopurinol did not change the FCU in healthy or gouty subjects. FCUs of patients with gout were lower than the FCUs of healthy subjects (4.8% versus 6.9%; P < 0.0001).Conclusions
The present studies indicate that the spot-FCU is a convenient, valid, and reliable indicator of the efficiency of the kidney in removing urate from the blood and thus from tissues. Spot-FCU determinations may provide useful correlates in studies investigating molecular mechanisms underpinning the observed range of efficiencies of the kidneys in clearing urate from the blood.Trial Registration
ACTRN12611000743965 相似文献218.
219.
Dubowitz T Ghosh-Dastidar M Eibner C Slaughter ME Fernandes M Whitsel EA Bird CE Jewell A Margolis KL Li W Michael YL Shih RA Manson JE Escarce JJ 《Obesity (Silver Spring, Md.)》2012,20(4):862-871
Using data (n = 60,775 women) from the Women's Health Initiative Clinical Trial (WHI CT)—a national study of postmenopausal women aged 50–79 years—we analyzed cross‐sectional associations between the availability of different types of food outlets in the 1.5 miles surrounding a woman's residence, census tract neighborhood socioeconomic status (NSES), BMI, and blood pressure (BP). We simultaneously modeled NSES and food outlets using linear and logistic regression models, adjusting for multiple sociodemographic factors, population density and random effects at the tract and metropolitan statistical area (MSA) level. We found significant associations between NSES, availability of food outlets and individual‐level measurements of BMI and BP. As grocery store/supermarket availability increased from the 10th to the 90th percentile of its distribution, controlling for confounders, BMI was lower by 0.30 kg/m2. Conversely, as fast‐food outlet availability increased from the 10th to the 90th percentile, BMI was higher by 0.28 kg/m2. When NSES increased from the 10th to the 90th percentile of its distribution, BMI was lower by 1.26 kg/m2. As NSES increased from the 10th to the 90th percentile, systolic and diastolic BP were lower by 1.11 mm Hg and 0.40 mm Hg, respectively. As grocery store/supermarket outlet availability increased from the 10th and 90th percentiles, diastolic BP was lower by 0.31 mm Hg. In this national sample of postmenopausal women, we found important independent associations between the food and socioeconomic environments and BMI and BP. These findings suggest that changes in the neighborhood environment may contribute to efforts to control obesity and hypertension. 相似文献
220.
Clive Slaughter 《Journal of biomolecular techniques》2009,20(3):186-189
This column highlights recently published articles that are of interest to the readership of this publication. We encourage ABRF members to forward information on articles they feel are important and useful to Clive Slaughter, MCG-UGA Medical Partnership, 285 S. Jackson Street, Athens, GA 30602; E-mail: cslaughter@mcg.edu, or to any member of the editorial board. Article summaries reflect the reviewer's opinions and not necessarily those of the Association. 相似文献