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Structure-based redesign of an edema toxin inhibitor.

ABSTRACT: Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3',5'-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an oral dosage of 15?g/mouse. Here, molecular docking was used to predict improvements in potency and solubility of new derivatives of compound 1 in inhibiting edema toxin (ET)-catalyzed stimulation of cyclic AMP production in murine monocyte-macrophage cells (RAW 264.7). Structure-activity relationship (SAR) analysis of the bioassay results for 22 compounds indicated positions important for activity. Several derivatives demonstrated superior pharmacological properties compared to our initial lead compound, and are promising candidates to treat anthrax infections and diarrheal diseases induced by toxin-producing bacteria.

SUBMITTER: Chen D

PROVIDER: S-EPMC3251925 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Structure-based redesign of an edema toxin inhibitor.

Chen Deliang D Ma Lili L Kanalas John J JJ Gao Jian J Pawlik Jennifer J Jimenez Maria Estrella ME Walter Mary A MA Peterson Johnny W JW Gilbertson Scott R SR Schein Catherine H CH

Bioorganic & medicinal chemistry 20111116 1

Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3',5'-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an ...[more]

PMID: 22154558

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Project description:MotivationDisruption of protein-protein interactions can mitigate antibody recognition of therapeutic proteins, yield monomeric forms of oligomeric proteins, and elucidate signaling mechanisms, among other applications. While designing affinity-enhancing mutations remains generally quite challenging, both statistically and physically based computational methods can precisely identify affinity-reducing mutations. In order to leverage this ability to design variants of a target protein with disrupted interactions, we developed the DisruPPI protein design method (DISRUpting Protein-Protein Interactions) to optimize combinations of mutations simultaneously for both disruption and stability, so that incorporated disruptive mutations do not inadvertently affect the target protein adversely.ResultsTwo existing methods for predicting mutational effects on binding, FoldX and INT5, were demonstrated to be quite precise in selecting disruptive mutations from the SKEMPI and AB-Bind databases of experimentally determined changes in binding free energy. DisruPPI was implemented to use an INT5-based disruption score integrated with an AMBER-based stability assessment and was applied to disrupt protein interactions in a set of different targets representing diverse applications. In retrospective evaluation with three different case studies, comparison of DisruPPI-designed variants to published experimental data showed that DisruPPI was able to identify more diverse interaction-disrupting and stability-preserving variants more efficiently and effectively than previous approaches. In prospective application to an interaction between enhanced green fluorescent protein (EGFP) and a nanobody, DisruPPI was used to design five EGFP variants, all of which were shown to have significantly reduced nanobody binding while maintaining function and thermostability. This demonstrates that DisruPPI may be readily utilized for effective removal of known epitopes of therapeutically relevant proteins.Availability and implementationDisruPPI is implemented in the EpiSweep package, freely available under an academic use license.Supplementary informationSupplementary data are available at Bioinformatics online.

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Structure-based redesign of an edema toxin inhibitor.

Publications

Structure-based redesign of an edema toxin inhibitor.

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