کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2563844 | 1127569 | 2013 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Inhibitors of Bacillus anthracis edema factor
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کلمات کلیدی
NTPPDEANTpKaACDadenylyl cyclase - آدنیلات سیکلاز، آدنیلیل سیکلازedema factor - ادم فاکتورFluorescence resonance energy transfer - انتقال انرژی رزونانس FluorescenceFRET - انتقال انرژی رزونانسی فورسترCAM - ساخت به کمک کامپیوترPhosphodiesterase - فسفو دی استرازFluorescence spectroscopy - فوتولومینسانس یا فلوئورسانس یا فسفرسانسMolecular modeling - مدل سازی مولکولیMANT - مناتMAC - مکnucleoside 5′-triphosphate - نوکلئوزید 5'-تری فسفاتcAMP-dependent protein kinase - پروتئین کیناز وابسته به cAMPCalmodulin - کالمودولین
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
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چکیده انگلیسی
Edema factor (EF) is a calmodulin (CaM)-activated adenylyl cyclase (AC) toxin from Bacillus anthracis that contributes to anthrax pathogenesis. Anthrax is an important medical problem, but treatment of B. anthracis infections is still unsatisfying. Thus, selective EF inhibitors could be valuable drugs in the treatment of anthrax infection, most importantly shock. The catalytic site of EF, the EF/CaM interaction site and allosteric sites constitute potential drug targets. To this end, most efforts have been directed towards targeting the catalytic site. A major challenge in the field is to obtain compounds with high selectivity for AC toxins relative to mammalian membranous ACs (mACs). 3â²-(N-methyl)anthraniloyl-2â²-deoxyadenosine-5â²-triphosphate is the most potent EF inhibitor known so far (Ki, 10Â nM), but selectivity relative to mACs needs to be improved (currently ~5-50-fold, depending on the specific mAC isoform considered). AC toxin inhibitors can be identified in virtual screening studies based on available EF crystal structures and examined in cellular test systems or at the level of purified toxin using classic radioisotopic or non-radioactive fluorescence assays. Binding of certain MANT-nucleotides to AC toxins elicits large direct fluorescence- or fluorescence resonance energy transfer signals upon interaction with CaM, and these signals can be used to identify toxin inhibitors in competition binding studies. Collectively, potent EF inhibitors are available, but before they can be used clinically, selectivity against mACs must be improved. However, several methodological approaches, complementing each other, are now available to direct the development of potent, selective, orally applicable and clinically useful EF inhibitors.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Pharmacology & Therapeutics - Volume 140, Issue 2, November 2013, Pages 200-212
Journal: Pharmacology & Therapeutics - Volume 140, Issue 2, November 2013, Pages 200-212
نویسندگان
Roland Seifert, Stefan Dove,