New verticilides, inhibitors of acyl-CoA:cholesterol acyltransferase, produced by Verticillium sp. FKI-2679

Ohshiro, Taichi; Matsuda, Daisuke; Takeuchi, Kazuhiro; Uchida, Ryuji; Nonaka, Kenichi; Masuma, Rokuro; Tomoda, Hiroshi

doi:10.1038/ja.2012.12

Cited by 20 publications

(14 citation statements)

References 34 publications

(47 reference statements)

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“…nat-(−)-verticilide was found to be an RyR antagonist, inhibiting insect RyR with an IC 50 value of 4.2 μM (35). Because insects have only one RyR isoform, (−)-verticilide is a promising lead for developing new insecticides (36). (−)-Verticilide weakly inhibits mouse RyR1 with an IC 50 value of 53.9 μM (35), but its affinity to mammalian RyR2 or RyR3 is unknown.…”

Section: Resultsmentioning

confidence: 99%

Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic

Batiste

Blackwell

Kim

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias in a variety of heart diseases and has also been implicated in neurodegenerative and seizure disorders, making RyR2 an attractive therapeutic target for drug development. Here we synthesized and investigated the fungal natural product and known insect RyR antagonist (−)-verticilide and several congeners to determine their activity against mammalian RyR2. Although the cyclooligomeric depsipeptide natural product (−)-verticilide had no effect, its nonnatural enantiomer [ent-(+)-verticilide] significantly reduced RyR2-mediated spontaneous Ca2+ leak both in cardiomyocytes from wild-type mouse and from a gene-targeted mouse model of Ca2+ leak-induced arrhythmias (Casq2−/−). ent-(+)-verticilide selectively inhibited RyR2-mediated Ca2+ leak and exhibited higher potency and a distinct mechanism of action compared with the pan-RyR inhibitors dantrolene and tetracaine and the antiarrhythmic drug flecainide. ent-(+)-verticilide prevented arrhythmogenic membrane depolarizations in cardiomyocytes without significant effects on the cardiac action potential and attenuated ventricular arrhythmia in catecholamine-challenged Casq2−/− mice. These findings indicate that ent-(+)-verticilide is a potent and selective inhibitor of RyR2-mediated diastolic Ca2+ leak, making it a molecular tool to investigate the therapeutic potential of targeting RyR2 hyperactivity in heart and brain pathologies. The enantiomer-specific activity and straightforward chemical synthesis of (unnatural) ent-(+)-verticilide provides a compelling argument to prioritize ent-natural product synthesis. Despite their general absence in nature, the enantiomers of natural products may harbor unprecedented activity, thereby leading to new scaffolds for probe and therapeutic development.

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Section: Resultsmentioning

confidence: 99%

Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic

Batiste

Blackwell

Kim

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…FKI-2679. These compounds showed inhibitory activity on acyl-CoA:cholesterol acyltransferase (ACAT) in a cell-based assay using ACAT1- and ACAT2-expressing CHO cells [ 179 ].…”

Section: Cyclic Octadepsipeptidesmentioning

confidence: 99%

Structural Diversity and Biological Activities of Cyclic Depsipeptides from Fungi

Wang

Gong

et al. 2018

Molecules

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Cyclic depsipeptides (CDPs) are cyclopeptides in which amide groups are replaced by corresponding lactone bonds due to the presence of a hydroxylated carboxylic acid in the peptide structure. These peptides sometimes display additional chemical modifications, including unusual amino acid residues in their structures. This review highlights the occurrence, structures and biological activities of the fungal CDPs reported until October 2017. About 352 fungal CDPs belonging to the groups of cyclic tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, and tridecadepsipeptides have been isolated from fungi. These metabolites are mainly reported from the genera Acremonium, Alternaria, Aspergillus, Beauveria, Fusarium, Isaria, Metarhizium, Penicillium, and Rosellina. They are known to exhibit various biological activities such as cytotoxic, phytotoxic, antimicrobial, antiviral, anthelmintic, insecticidal, antimalarial, antitumoral and enzyme-inhibitory activities. Some CDPs (i.e., PF1022A, enniatins and destruxins) have been applied as pharmaceuticals and agrochemicals.

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“…Similarly, the accumulation of TG in adipocytes can lead to obesity and thus contributes to fat formation in all obesity syndromes 4 . We are interested in discovering microbial inhibitors of neutral lipid synthesis/accumulation using a variety of cell-based assays with mouse peritoneal macrophages 5 – 12 , Raji cells 13 , and CHO cells expressing sterol O -acyltransferase (SOAT, also known as acyl-CoA: cholesterol acyltransferase (ACAT)) 14 – 18 , among others.…”

Section: Introductionmentioning

confidence: 99%

A Mixture of Atropisomers Enhances Neutral Lipid Degradation in Mammalian Cells with Autophagy Induction

Kobayashi

Ohte

Ohshiro

et al. 2018

Sci Rep

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Atropisomers with a biaryl dihydronaphthopyranone structure, dinapinones A1 (DPA1) (M position) and A2 (DPA2) (P position), were isolated from the fungus culture broth of Talaromyces pinophilus FKI-3864 as inhibitors of [14C]neutral lipid ([14C]triacylglycerol (TG) and [14C]cholesteryl ester (CE)) synthesis from [14C]oleic acid in Chinese hamster ovary-K1 (CHO-K1) cells. DPA2 inhibited [14C]TG and [14C]CE synthesis (IC50s, 0.65 and 5.6 μM, respectively), but DPA1 had no inhibitory activity on [14C]TG and [14C]CE synthesis even at 12 μM. However, a 1:1 mixture of DPA1 and DPA2 (DPAmix) had the most potent inhibitory activity on [14C]TG and [14C]CE synthesis (IC50s, 0.054 and 0.18 μM, respectively). The mechanism of action of DPAmix was investigated. DPAmix had no effects on the enzymes involved in neutral lipid synthesis, while DPAmix enhanced the degradation of [14C]neutral lipids with concomitant decrease in cytosolic lipid droplets accumulated in CHO-K1 cells. From analysis of autophagy marker proteins, DPAmix caused dose-dependent induction of microtubule-associated protein light chain 3-II (LC3-II) and degradation of p62. In the autophagic flux assay using bafilomycin A1, DPAmix upregulated autophagosome turnover. These results reveal that DPAmix enhances neutral lipid degradation together with induction of autophagy.

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New verticilides, inhibitors of acyl-CoA:cholesterol acyltransferase, produced by Verticillium sp. FKI-2679

Cited by 20 publications

References 34 publications

Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic

Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic

Structural Diversity and Biological Activities of Cyclic Depsipeptides from Fungi

A Mixture of Atropisomers Enhances Neutral Lipid Degradation in Mammalian Cells with Autophagy Induction

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