Structure-based redesign of an edema toxin inhibitor

Chen, Deliang; Ma, Lili; Kanalas, John J.; Gao, Jian; Pawlik, Jennifer; Jimenez, Maria Estrella; Walter, Mary Ann; Peterson, Johnny W.; Gilbertson, Scott R.; Schein, Catherine H.

doi:10.1016/j.bmc.2011.10.091

Cited by 10 publications

(12 citation statements)

References 28 publications

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“…For example, β‐lactam antibiotics can increase the production of bacterial toxins in Staphylococcus aureus , while those that inhibit protein synthesis, such as clindamycin, greatly reduce them . As toxins mediate pathogenic effects even after the death of the bacteria, direct inhibitors of bacterial toxins may aid in controlling symptoms when used alone or in combination with antibiotics . Further, as discussed in the next sections, patients may benefit from alternative application modes and cotreatment with antibiotics and other compounds designed to directly target pathways in human cells.…”

Section: Finding New Uses For Approved Drugsmentioning

confidence: 99%

Repurposing approved drugs on the pathway to novel therapies

Schein

2019

Medicinal Research Reviews

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The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

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Section: Finding New Uses For Approved Drugsmentioning

confidence: 99%

Repurposing approved drugs on the pathway to novel therapies

Schein

2019

Medicinal Research Reviews

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“…As a result, 19 best-scored compounds were tested in a cell assay for their ability to reduce cAMP secretion induced by EF, and it was found that four structurally different compounds inhibited EF in the low micromolar range. Recently, the same group published a study aiming to redesign one of the several initial “hits”, (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid) or DC-5 (also refereed as compound 1 and FIV-50), to search for derivatives that would have similar or better activity, improved aqueous solubility, and reduced toxicity (159). Molecular docking was used to predict the potency and solubility of the new derivatives.…”

Section: Pa Lf and Ef As Antitoxin Design Targetsmentioning

confidence: 99%

“…Left : Structure of compound 22, one of the (M)ANT nucleotides inhibiting with IC 50 = 10 nM (157). Right : Structure for an optimized EF inhibitor, compound 22 (159) inhibiting EF-induced secretion of cAMP by cultured cells with IC 50 = 2.71 μM.…”

Section: Article Highlightsmentioning

confidence: 99%

Designing inhibitors of anthrax toxin

Nestorovich

Bezrukov

2014

Expert Opinion on Drug Discovery

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Introduction Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates, and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded “for the development of multiscale models for complex chemical systems” once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial and error approach to a minimum. The “rational drug design” term is rather comprehensive as it includes all contemporary methods of drug discovery where serendipity and screening are substituted by the information-guided search for new and existing compounds. Successful implementation of these innovative drug discovery approaches is inevitably preceded by learning the physics, chemistry, and physiology of functioning of biological structures under normal and pathological conditions. Areas covered This article provides an overview of the recent rational drug design approaches to discover inhibitors of anthrax toxin. Some of the examples include small-molecule and peptide-based post-exposure therapeutic agents as well as several polyvalent compounds. The review also directs the reader to the vast literature on the recognized advances and future possibilities in the field. Expert opinion Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (PA-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, in our view, the situation is still insecure. The FDA’s animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Besides, unlike PA, which is known to be unstable, LF remains active in cells and in animal tissues for days. Therefore, the effectiveness of the post-exposure treatment of the individuals with anti-PA therapeutics can be time-dependent, requiring coordinated use of membrane permeable small-molecule inhibitors, which block the LF and EF enzymatic activity intracellularly. The desperate search for an ideal anthrax antitoxin allowed researchers to gain important knowledge of the basic principles of small-molecule interactions with their protein targets that could be easily transferred to other systems. At the same time, better identification and validation of anthrax toxin therapeutic targets at the molecular level, which include understanding of the physical forces underlying the target/drug interaction, as well as elucidation of the parameters determining the corresponding therapeutic windows, require further examination.

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“…While there was no obvious toxicity to the mice, there was some indication of cytotoxic potential in the “Green Screen” assay at levels 10–20× the active concentration. Our initial results indicated that the fluorenone ring contributed to the inhibitory activity [36], and thus, most of the derivatives synthesized targeted the benzoic acid side chain, which had some markers of toxicity [37]. We were able to identify several derivatives with better predicted pharmaceutical properties, and equivalent or better activity in the bioassay for cAMP production induced by treatment of mammalian cells with ET.…”

Section: Redesign Of the Inhibitors For Enhanced Solubility And Rementioning

confidence: 99%

“…We thus considered that this group should bind in a similar position as the phosphate oxygens of 3'-dATP, and that it would be essential for activity. Further docking analysis of the compound containing the carbamimidoylphenyl derivative indicated that this side chain could target another, negatively charged area of the active site that we had not included in the initial pharmacophore, specifically the backbone oxygen atoms from the residues of Lys346, Gly347, Val350 and carboxyl group of Asp491 [37]. The carbamimidoylphenyl derivative, as it has a lower clogP than compound 1, and no markers of toxicity, has now been included for future animal testing.…”

Section: Redesign Of the Inhibitors For Enhanced Solubility And Rementioning

confidence: 99%

Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor

Schein

Chen

et al. 2012

Toxins

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Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. Stable and easily stored inhibitors of the edema factor toxin (EF), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin’s basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity. While nucleotide based inhibitors, similar to its natural substrate, ATP, were identified early, these compounds had low activity and specificity for EF. We used a combined structural and computational approach to choose small organic molecules in large, web-based compound libraries that would, based on docking scores, bind to residues within the substrate binding pocket of EF. A family of fluorenone-based inhibitors was identified that inhibited the release of cAMP from cells treated with EF. The lead inhibitor was also shown to inhibit the diarrhea caused by enterotoxigenic E. coli (ETEC) in a murine model, perhaps by serving as a quorum sensor. These inhibitors are now being tested for their ability to inhibit Anthrax infection in animal models and may have use against other pathogens that produce toxins similar to EF, such as Bordetella pertussis or Vibrio cholera.

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Structure-based redesign of an edema toxin inhibitor

Cited by 10 publications

References 28 publications

Repurposing approved drugs on the pathway to novel therapies

Repurposing approved drugs on the pathway to novel therapies

Designing inhibitors of anthrax toxin

Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor

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