ArticleMolecular pharmacology2009
Molecular analysis of the interaction of anthrax adenylyl cyclase toxin, edema factor, with 2'(3')-O-(N-(methyl)anthraniloyl)-substituted purine and pyrimidine nucleotides.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 37 citations in OpenAlex.
- Acyclic nucleoside phosphonates with 2-aminothiazole base as inhibitors of bacterial and mammalian adenylate cyclases.European journal of medicinal chemistry · 2021Article
- AnalyzingFrontiers in molecular biosciences · 2020Article
- Review
- Different Roles of N-Terminal and C-Terminal Domains in Calmodulin for Activation of Bacillus anthracis Edema Factor.Toxins · 2015Article
- An overview of investigational toxin-directed therapies for the adjunctive management of Bacillus anthracis infection and sepsis.Expert opinion on investigational drugs · 2015Review
- Effects of 39 Compounds on Calmodulin-Regulated Adenylyl Cyclases AC1 and Bacillus anthracis Edema Factor.PloS one · 2015Article
- Designing inhibitors of anthrax toxin.Expert opinion on drug discovery · 2014Review
- Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes.Nature medicine · 2013Article
- Article
- Article
- Small molecule inhibitors of Bacillus anthracis protective antigen proteolytic activation and oligomerization.Journal of medicinal chemistry · 2012Article
- Review
- Bacillus anthracis edema factor substrate specificity: evidence for new modes of action.Toxins · 2012Review
- Inhibition of the adenylyl cyclase toxin, edema factor, from Bacillus anthracis by a series of 18 mono- and bis-(M)ANT-substituted nucleoside 5'-triphosphates.Naunyn-Schmiedeberg's archives of pharmacology · 2012Article
- Structure-activity relationships for the interactions of 2'- and 3'-(O)-(N-methyl)anthraniloyl-substituted purine and pyrimidine nucleotides with mammalian adenylyl cyclases.Biochemical pharmacology · 2011Article
- Structural basis for the high-affinity inhibition of mammalian membranous adenylyl cyclase by 2',3'-o-(N-methylanthraniloyl)-inosine 5'-triphosphate.Molecular pharmacology · 2011Article
- Effect of MANT-nucleotides on L-type calcium currents in murine cardiomyocytes.Naunyn-Schmiedeberg's archives of pharmacology · 2011Article
- Pharmacological characterization of adenylyl cyclase isoforms in rabbit kidney membranes.Naunyn-Schmiedeberg's archives of pharmacology · 2011Article
- Bis-halogen-anthraniloyl-substituted nucleoside 5'-triphosphates as potent and selective inhibitors of Bordetella pertussis adenylyl cyclase toxin.The Journal of pharmacology and experimental therapeutics · 2011Article
- New developments in vaccines, inhibitors of anthrax toxins, and antibiotic therapeutics for Bacillus anthracis.Current medicinal chemistry · 2011Review
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Bacillus anthracis causes anthrax disease and exerts its deleterious effects by the release of three exotoxins: lethal factor, protective antigen, and edema factor (EF), a highly active calmodulin-dependent adenylyl cyclase (AC). However, conventional antibiotic treatment is ineffective against either toxemia or antibiotic-resistant strains. Thus, more effective drugs for anthrax treatment are needed. Previous studies from our laboratory showed that mammalian membranous AC (mAC) exhibits broad specificity for purine and pyrimidine nucleotides ( Mol Pharmacol 70: 878-886, 2006 ). Here, we investigated structural requirements for EF inhibition by natural purine and pyrimidine nucleotides and nucleotides modified with N-methylanthraniloyl (MANT)- or anthraniloyl groups at the 2'(3')-O-ribosyl position. MANT-CTP was the most potent EF inhibitor (K(i), 100 nM) among 16 compounds studied. MANT-nucleotides inhibited EF competitively. Activation of EF by calmodulin resulted in effective fluorescence resonance energy transfer (FRET) from tryptophan and tyrosine residues located in the vicinity of the catalytic site to MANT-ATP, but FRET to MANT-CTP was only small. Mutagenesis studies revealed that Phe586 is crucial for FRET to MANT-ATP and MANT-CTP and that the mutations N583Q, K353A, and K353R differentially alter the inhibitory potencies of MANT-ATP and MANT-CTP. Docking approaches relying on crystal structures of EF indicate similar binding modes of the MANT nucleotides with subtle differences in the region of the nucleobases. In conclusion, like mAC, EF accommodates both purine and pyrimidine nucleotides. The unique preference of EF for the base cytosine offers an excellent starting point for the development of potent and selective EF inhibitors.
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