The intriguing chemistry and biology of soraphens

Naini, Arun; Sasse, Florenz; Brönstrup, Mark

doi:10.1039/c9np00008a

Cited by 20 publications

(12 citation statements)

References 75 publications

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“…Soraphen A (Figure ) is metabolite from the myxobacteria Sorangium cellulosum , originally investigated as a fungicide by Ciba-Geigy . In addition to its fungicidal activity, soraphen A, and its family of analogs, has also been useful as a probe for a range of clinical disorders including cancer and autoimmune and liver diseases . Unfortunately, soraphen A and its analogs have not yet proved useful as fungicides, nor have they successfully been used as inspiration for NPMs.…”

Section: Future Opportunitiesmentioning

confidence: 99%

“…222 In addition to its fungicidal activity, soraphen A, and its family of analogs, has also been useful as a probe for a range of clinical disorders including cancer and autoimmune and liver diseases. 223 Unfortunately, soraphen A and its analogs have not yet proved useful as fungicides, nor have they successfully been used as inspiration for NPMs. Interestingly, recent studies using soraphen A as a model for binding in the BC domain of human acetyl CoA carboxylase (hACC) have subsequently resulted in the identification of highly potent, simplified synthetic hACC inhibitors (Figure 25).…”

Section: Future Opportunitiesmentioning

confidence: 99%

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Structure Simplification of Natural Products as a Lead Generation Approach in Agrochemical Discovery

Sparks¹,

Duke

2021

J. Agric. Food Chem.

103

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Natural products (NPs) have a long history as sources of compounds for crop protection. Perhaps a more important role for NPs has been as models and inspiration for the discovery and development of synthetic crop protection compounds. NPs and their synthetic mimics account for 18% of all crop protection compounds, whereas another 38% of all crop protection compounds have a NP that could have served as a model. Because NPs are often complex molecules, have limited availability, or possess structural features that constrain their suitability for use in agricultural settings, a key element in NP-inspired compounds is the simplification of the NP structure to provide a synthetically accessible molecule that possesses the physicochemical properties needed for use in crop protection. Herein we review a series of examples of NP mimics that demonstrate the structural or synthetic simplification of NPs as a guide for the discovery of future NP-inspired agrochemicals focused on fungicides, herbicides, and insecticides.

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Section: Future Opportunitiesmentioning

confidence: 99%

Section: Future Opportunitiesmentioning

confidence: 99%

Structure Simplification of Natural Products as a Lead Generation Approach in Agrochemical Discovery

Sparks¹,

Duke

2021

J. Agric. Food Chem.

103

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“…Soraphen was the first prominent lead compound isolated from myxobacteria, before epothilones gained worldwide attention. Now it continues to show the application prospect for viral or autoimmune diseases (Naini et al 2019). Therefore, screening and isolating new biologically active compounds from myxobacteria is of great significance.…”

Section: Introductionmentioning

confidence: 99%

“…Now it continues to show the application prospect for viral or autoimmune diseases (Naini et al . 2019). Therefore, screening and isolating new biologically active compounds from myxobacteria is of great significance.…”

Section: Introductionmentioning

confidence: 99%

The synergistic antifungal activity of resveratrol with azoles against Candida albicans

Wang

Zhang

Gao

et al. 2021

Letters Applied Microbiology

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Candida albicans is one of the most common clinical pathogenic microorganisms and it is becoming a serious health threat, particularly to immunocompromised populations. Drug resistance of Candida species has also frequently emerged, and combination therapy for fungal infections has attracted considerable attention. In this study, we established the Qinling Mountains myxobacterial secondary metabolites library and a synergic assay in combination with ketoconazole against C. albicans was introduced for metabolites screening. Two active compounds with synergic anticandidal activities were obtained, which were identified as trans‐resveratrol and cis‐resveratrol. According to our study, resveratrol can reduce the dosage to 1/64 of ketoconazole as well as itraconazole. Furthermore, synergistic anticandidal activity of resveratrol combined with azoles was verified against a panel of clinical C. albicans isolates, and the combination strategy enhanced the azoles susceptibility of three fluconazole‐resistant isolates. These findings suggest that resveratrol enhances the efficacy of azoles and provides a promising application in therapy of C. albicans infection.

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“…Soraphen A (SorA), a macrolide natural product produced by the myxobacterium Sorangium cellulosum , has been recently shown to have anticancer, immune-modulatory, and antiviral activities. − SorA is a potent inhibitor of acetyl-CoA carboxylase (ACC), thereby interfering with fatty acid metabolism. The validity of ACC inhibition as a host-directed antiviral target has been shown with SorA in cellular models of hepatitis C virus (HCV) and human immunodeficiency virus (HIV). − Synthetic inhibitors of the catalytic site of ACC have been recently shown to inhibit Flaviviridae like DENV, West Nile virus, or Zika virus in cellular models with low micromolar potency. , As SorA exerts a superior inhibitory potency against ACC, we probed its efficacy against DENV in this study.…”

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confidence: 99%

Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Treatment of Dengue Infections Applied to the Broad Spectrum Antiviral Soraphen A

Heyner

Krull

Harmrolfs

et al. 2021

ACS Pharmacol. Transl. Sci.

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While a drug treatment is unavailable, the global incidence of Dengue virus (DENV) infections and its associated severe manifestations continues to rise. We report the construction of the first physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that predicts viremia levels in relevant target organs based on preclinical data with the broad spectrum antiviral soraphen A (SorA), an inhibitor of the host cell target acetyl-CoA-carboxylase. SorA was highly effective against DENV in vitro (EC50 = 4.7 nM) and showed in vivo efficacy by inducing a significant reduction of viral load in the spleen and liver of IFNAR–/– mice infected with DENV-2. PBPK/PD predictions for SorA matched well with the experimental infection data. Transfer to a human PBPK/PD model for DENV to mimic a clinical scenario predicted a reduction in viremia by more than one log10 unit for an intravenous infusion regimen of SorA. The PBPK/PD model is applicable to any DENV drug lead and, thus, represents a valuable tool to accelerate and facilitate DENV drug discovery and development.

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The intriguing chemistry and biology of soraphens

Abstract: Soraphens, discovered from the myxobacterial strain Sorangium cellulosum, have intrigued chemists and biologists due to their diverse biological effects mediated by the potent inhibition of acetyl CoA carboxylase.

Cited by 20 publications

References 75 publications

Structure Simplification of Natural Products as a Lead Generation Approach in Agrochemical Discovery

Structure Simplification of Natural Products as a Lead Generation Approach in Agrochemical Discovery

The synergistic antifungal activity of resveratrol with azoles against Candida albicans

Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Treatment of Dengue Infections Applied to the Broad Spectrum Antiviral Soraphen A

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