1,720,956 research outputs found
Developing Novel Chlamydia-Targeted Protease Inhibitors
No full textChlamydia trachomatis is an obligate intracellular human parasite responsible for the most common sexually transmitted bacterial infection world-wide. The largely asymptomatic infection frequently results in complications including ectopic pregnancy, infertility and reversible blindness. The mainstay therapy for chlamydia is the use of macrolide antibiotics such as azithromycin and erythromycin. While these drugs are currently effective, there are growing concerns about their efficacy due to the ever-increasing prevalence of the disease, coupled with the fact that the drugs are general antibacterials with no pre-designed specificity for Chlamydia which is an atypical bacterium. This necessitates the timely search for Chlamydia-targeted drugs with new mechanisms of action.
C. trachomatis high temperature requirement A protease (CtHtrA) is a serine protease identified to be crucial for the survival and virulence of Chlamydia in the human body, and a viable drug target. JO146 (Boc-Val-Pro-ValP(OPh)2), a mixture of two diastereomers with R-/S-Val at P1, was previously identified as a covalent inhibitor of CtHtrA (IC50 = 12.5 µM) that is selectively toxic to human and koala pathogenic Chlamydia species. However, JO146 is not potent enough and may also be susceptible to enzymatic degradation, being a peptide-based compound.
The present study explored different avenues to improve the potency and selectivity of JO146, as well as reduce its peptidic nature. The influence of the stereochemical difference between the two diastereomers of JO146 on their anti-chlamydial activity was examined. Inhibitors containing different covalent and noncovalent reversible transition state analogues of the phosphonate moiety were synthesized and tested in in vitro enzyme inhibition and Chlamydia cell culture assays. Analogues with significant anti-chlamydial activity were identified and further optimized by improving their binding affinity at the various subpockets of CtHtrA.
JO146-D2, the isomer with the physiologically relevant R-Val at P1 had significantly better anti-chlamydial activity over JO146-D1, the isomer with the S-Val at P1 (> 100-fold increase). Both compounds had excellent selectivity for CtHtrA over the potential off-target serine proteases trypsin and chymotrypsin. Noncovalent binders, which include the N-methylamide, valinol and N-methyl imidazole analogues of JO146 were generally devoid of activity, inferring the necessity of covalent interactions for activity. Of the tested reversible covalent inhibitors, only the prime side-binding α-ketobenzothiazole analogue displayed viable anti-chlamydial activity. Binding optimization to CtHtrA revealed isoleucine and tertiary leucine to be the most active residues at P1 and P3 respectively, yielding a new lead molecule Boc-Tle-Pro-IleP(OPh)2 which had approximately 1000-fold increase in cellular anti-chlamydial activity relative to JO146. Additionally, a good number of these inhibitors showed improved selectivity for CtHtrA over the structurally close human neutrophil elastase, compared to the lead molecule JO146.
In summary, more potent and potentially safe analogues of JO146 suitable for in vivo pre-clinical studies have been discovered. In addition, comprehensive structure activity relationships that would enable the design of clinically relevant inhibitors for the treatment of chlamydial infections were built in this study
Developing Novel Chlamydia-Targeted Protease Inhibitors
No full textChlamydia trachomatis is an obligate intracellular human parasite responsible for the most common sexually transmitted bacterial infection world-wide. The largely asymptomatic infection frequently results in complications including ectopic pregnancy, infertility and reversible blindness. The mainstay therapy for chlamydia is the use of macrolide antibiotics such as azithromycin and erythromycin. While these drugs are currently effective, there are growing concerns about their efficacy due to the ever-increasing prevalence of the disease, coupled with the fact that the drugs are general antibacterials with no pre-designed specificity for Chlamydia which is an atypical bacterium. This necessitates the timely search for Chlamydia-targeted drugs with new mechanisms of action.
C. trachomatis high temperature requirement A protease (CtHtrA) is a serine protease identified to be crucial for the survival and virulence of Chlamydia in the human body, and a viable drug target. JO146 (Boc-Val-Pro-ValP(OPh)2), a mixture of two diastereomers with R-/S-Val at P1, was previously identified as a covalent inhibitor of CtHtrA (IC50 = 12.5 µM) that is selectively toxic to human and koala pathogenic Chlamydia species. However, JO146 is not potent enough and may also be susceptible to enzymatic degradation, being a peptide-based compound.
The present study explored different avenues to improve the potency and selectivity of JO146, as well as reduce its peptidic nature. The influence of the stereochemical difference between the two diastereomers of JO146 on their anti-chlamydial activity was examined. Inhibitors containing different covalent and noncovalent reversible transition state analogues of the phosphonate moiety were synthesized and tested in in vitro enzyme inhibition and Chlamydia cell culture assays. Analogues with significant anti-chlamydial activity were identified and further optimized by improving their binding affinity at the various subpockets of CtHtrA.
JO146-D2, the isomer with the physiologically relevant R-Val at P1 had significantly better anti-chlamydial activity over JO146-D1, the isomer with the S-Val at P1 (> 100-fold increase). Both compounds had excellent selectivity for CtHtrA over the potential off-target serine proteases trypsin and chymotrypsin. Noncovalent binders, which include the N-methylamide, valinol and N-methyl imidazole analogues of JO146 were generally devoid of activity, inferring the necessity of covalent interactions for activity. Of the tested reversible covalent inhibitors, only the prime side-binding α-ketobenzothiazole analogue displayed viable anti-chlamydial activity. Binding optimization to CtHtrA revealed isoleucine and tertiary leucine to be the most active residues at P1 and P3 respectively, yielding a new lead molecule Boc-Tle-Pro-IleP(OPh)2 which had approximately 1000-fold increase in cellular anti-chlamydial activity relative to JO146. Additionally, a good number of these inhibitors showed improved selectivity for CtHtrA over the structurally close human neutrophil elastase, compared to the lead molecule JO146.
In summary, more potent and potentially safe analogues of JO146 suitable for in vivo pre-clinical studies have been discovered. In addition, comprehensive structure activity relationships that would enable the design of clinically relevant inhibitors for the treatment of chlamydial infections were built in this study
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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