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111.
Blum A Böttcher J Sammet B Luksch T Heine A Klebe G Diederich WE 《Bioorganic & medicinal chemistry》2008,16(18):8574-8586
Due to the important role that aspartic proteases play in many patho-physiological processes, they have intensively been targeted by modern drug development. However, up to now, only for two family members, renin and HIV protease, approved drugs are available. Inhibitor development, mostly guided by mimicking the natural peptide substrates, resulted in very potent inhibitors for several targets, but the pharmacokinetic properties of these compounds were often not optimal. Herein we report a novel approach for lead structure discovery of non-peptidic aspartic protease inhibitors using easily accessible achiral linear oligoamines as starting point. An initial library comprising 11 inhibitors was developed and screened against six selected aspartic proteases. Several hits could be identified, among them selective as well as rather promiscuous inhibitors. The design concept was confirmed by determination of the crystal structure of two derivatives in complex with the HIV-1 protease, and represents a promising basis for the further inhibitor development. 相似文献
112.
Ralf Krumkamp Nimako Sarpong Norbert Georg Schwarz Julia Adelkofer Wibke Loag Daniel Eibach Ralf Matthias Hagen Yaw Adu-Sarkodie Egbert Tannich Jürgen May 《PLoS neglected tropical diseases》2015,9(3)
IntroductionDiarrheal diseases are among the most frequent causes of morbidity and mortality in children worldwide, especially in resource-poor areas. This case-control study assessed the associations between gastrointestinal infections and diarrhea in children from rural Ghana.MethodsStool samples were collected from 548 children with diarrhea and from 686 without gastrointestinal symptoms visiting a hospital from 2007–2008. Samples were analyzed by microscopy and molecular methods.ResultsThe organisms most frequently detected in symptomatic cases were Giardia lamblia, Shigella spp./ enteroinvasive Escherichia coli (EIEC), and Campylobacter jejuni. Infections with rotavirus (adjusted odds ratio [aOR] = 8.4; 95% confidence interval [CI]: 4.3–16.6), C. parvum/hominis (aOR = 2.7; 95% CI: 1.4–5.2) and norovirus (aOR = 2.0; 95%CI: 1.3–3.0) showed the strongest association with diarrhea. The highest attributable fractions (AF) for diarrhea were estimated for rotavirus (AF = 14.3%; 95% CI: 10.9–17.5%), Shigella spp./EIEC (AF = 10.5%; 95% CI: 3.5–17.1%), and norovirus (AF = 8.2%; 95% CI 3.2–12.9%). Co-infections occurred frequently and most infections presented themselves independently of other infections. However, infections with E. dispar, C. jejuni, and norovirus were observed more often in the presence of G. lamblia.ConclusionsDiarrheal diseases in children from a rural area in sub-Saharan Africa are mainly due to infections with rotavirus, Shigella spp./EIEC, and norovirus. These associations are strongly age-dependent, which should be considered when diagnosing causes of diarrhea. The presented results are informative for both clinicians treating gastrointestinal infections as well as public health experts designing control programs against diarrheal diseases. 相似文献
113.
Kanika Vanshylla Veronica Di Cristanziano Franziska Kleipass Felix Dewald Philipp Schommers Lutz Gieselmann Henning Gruell Maike Schlotz Meryem S. Ercanoglu Ricarda Stumpf Petra Mayer Matthias Zehner Eva Heger Wibke Johannis Carola Horn Isabelle Suárez Norma Jung Susanne Salomon Florian Klein 《Cell host & microbe》2021,29(6):917-929.e4
114.