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The cyclic depsipeptide FR900359 (FR) is derived from the soil bacterium Chromobacterium vaccinii and known to bind Gq proteins of mammals and insects, thereby abolishing the signal transduction of their Gq protein-coupled receptors, a process that leads to severe physiological consequences. Due to their highly conserved structure, Gq family of proteins are a superior ecological target for FR producing organisms, resulting in a defense towards a broad range of harmful organisms. Here, we focus on the question whether bacteria like C. vaccinii are important factors in soil in that their secondary metabolites impair, e.g., plant harming organisms like nematodes. We prove that the Gq inhibitor FR is produced under soil-like conditions. Furthermore, FR inhibits heterologously expressed Gαq proteins of the nematodes Caenorhabditis elegans and Heterodera schachtii in the micromolar range. Additionally, in vivo experiments with C. elegans and the plant parasitic cyst nematode H. schachtii demonstrated that FR reduces locomotion of C. elegans and H. schachtii. Finally, egg-laying of C. elegans and hatching of juvenile stage 2 of H. schachtii from its cysts is inhibited by FR, suggesting that FR might reduce nematode dispersion and proliferation. This study supports the idea that C. vaccinii and its excreted metabolome in the soil might contribute to an ecological equilibrium, maintaining and establishing the successful growth of plants. [ABSTRACT FROM AUTHOR]

The biological activity of natural products YM-254890 (YM) and FR900359 (FR) has led to significant interest in both their synthesis and the construction of more simplified analogs. While the simplified analogs lose much of the potency of the natural products, they are of interest in their own right, and their synthesis has revealed synthetic barriers to the family of molecules that need to be addressed if a scalable synthesis of YM and FR analogs is to be constructed. In the work described here, a synthetic route to simplified analogs of YM is examined and strategies for circumventing some of the challenges inherent to constructing the molecules are forwarded. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) transfer extracellular signals across cell membranes by activating intracellular heterotrimeric G proteins. Several studies suggested G proteins as novel drug targets for the treatment of complex diseases, e.g., asthma and cancer. Recently, we developed specific radiotracers, [³H]PSB-15900-FR and [³H]PSB-16254-YM, for the Gαq family of G proteins by tritiation of the macrocyclic natural products FR900359 (FR) and YM-254890 (YM). In the present study, we utilized these potent radioligands to perform autoradiography studies in tissues of healthy mice, mouse models of disease, and human tissues. Specific binding was high, while non-specific binding was extraordinarily low, giving nearly identical results for both radioligands. High expression levels of Gαq proteins were detected in healthy mouse organs showing the following rank order of potency: kidney > liver > brain > pancreas > lung > spleen, while expression in the heart was low. Organ sub-structures, e.g., of mouse brain and lung, were clearly distinguishable. Whereas an acute asthma model in mice did not result in altered Gαq protein expressions as compared to control animals, a cutaneous melanoma model displayed significantly increased expression in comparison to healthy skin. These results suggest the future development of Gαq-protein-binding radio-tracers as novel diagnostics. [ABSTRACT FROM AUTHOR]

Access to the cyclic depsipeptide FR900359 (FR), a selective Gq/11 protein inhibitor of high pharmacological interest and a potential lead molecule for targeted therapy of cancers with oncogenic GNAQ or GNA11 mutations (encoding Gq and G11 respectively), has been challenging ever since its initial discovery more than three decades ago. The recent discovery of Chromobacterium vaccinii as a cultivable FR producer enables the development of approaches leading to a high‐yielding, scalable and sustainable biotechnological process for production of FR, thereby removing this bottleneck. Here we characterize different promoters in exchange of the native promoter of the FR assembly line, resulting in an overexpression mutant with significantly increased production of FR. Thereby, the isolation and structure elucidation of novel FR analogs of low abundance is enabled. Further, we explore the antiproliferative activities of fifteen chromodepsins against uveal melanoma cell lines harboring Gq/11 mutations and characterize the major metabolite of FR formed in plasma. [ABSTRACT FROM AUTHOR]

G proteins are key mediators of G protein‐coupled receptor (GPCR) signaling, facilitating a plethora of important physiological processes. The role of G proteins is much less understood than other aspects of GPCR function, which is largely due to the shortage of potent and selective G protein inhibitors. The natural cyclic depsipeptides YM‐254890 and FR900359 are two of the very few known selective inhibitors of the Gq subfamily, and are used as unique pharmacological tools in the study of G q‐mediated signaling. Moreover, a peptide‐based G protein antagonist‐2A (GP‐2A), a 27‐residue peptide (27mer(I860A)) derived from phospholipase C‐β3 (PLC‐β3), and the small molecule BIM‐46187 have also been characterized as selective G q inhibitors within the past 5 years. In this review, we highlight the recent development in chemical syntheses, characterization, and mechanism of action of these selective G q inhibitors. The development and application of G q‐selective inhibitors will expand our knowledge of the structure and function of G protein‐mediated signaling, shed light on the development of inhibitors for other G protein classes, and feed in to drug discovery for diseases where G proteins are implicated, including various forms of cancer. [ABSTRACT FROM AUTHOR]

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Abstract: The cyclic depsipeptide FR900359 (FR), isolated from the tropical plant Ardisia crenata, is a strong and selective inhibitor of Gq proteins, making it an indispensable pharmacological tool to study Gq‐related processes, as well as a promising drug candidate. Gq inhibition is a novel mode of action for defense chemicals and crucial for the ecological function of FR, as shown by in vivo experiments in mice, its affinity to insect Gq proteins, and insect toxicity studies. The uncultured endosymbiont of A. crenata was sequenced, revealing the FR nonribosomal peptide synthetase (frs) gene cluster. We here provide a detailed model of FR biosynthesis, supported by in vitro enzymatic and bioinformatic studies, and the novel analogue AC‐1, which demonstrates the flexibility of the FR starter condensation domains. Finally, expression of the frs genes in E. coli led to heterologous FR production in a cultivable, bacterial host for the first time. [ABSTRACT FROM AUTHOR]

A cyclic depsipeptide, FR900359, isolated from Ardisia crenata was evaluated for vasorelaxant effects on rat aortic arteries. FR900359 caused concentration-dependent relaxation (1 nM-10 μM) in phenylephrine-precontracted endothelium-intact aortic rings, which was inhibited by addition of l-NMMA, a NOS inhibitor. In endothelium-denuded rings, the relaxant effect of low concentrations of FR900359 was diminished, but remained at high concentrations. In endothelium-denuded rings, FR900359 at 0.1 μM significantly attenuated high-K-induced contractions and completely inhibited Ca-induced contractions. These results suggest that the vasorelaxant effect of FR900359 is mediated through the increased release of NO from endothelial cells at low concentrations, and can be attributed to inhibitory effects on voltage-dependent Ca channel- and receptor-operated Ca channel-dependent Ca influx at high concentrations. [ABSTRACT FROM AUTHOR]