The History of Alamethicin: A Review of the Most Extensively Studied Peptaibol

Leitgeb, Balázs; Szekeres, András; László, Manczinger; Vagvoelgyi, Csaba; Kredics, László

doi:10.1002/chin.200739264

Cited by 40 publications

(61 citation statements)

References 76 publications

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“…T2, the fungus was grown in several types of broth media. Growth of the fungus in a modified potato dextrose broth (PDB) resulted in the generation of numerous new and known members of the malettinin family of polyketides [malettinins A (27), B (28), and F-H (16)(17)(18)(19)(20), respectively] ( Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

“…The peptaibols have been intensively studied because of their abilities to form pores in the outer membranes of cells; these pore-forming capabilities result in most compounds in this class exhibiting nonspecific cytotoxic properties toward bacterial, fungal, and mammalian cells (15,17). The effects of peptaibols on mammalian cells tend to be relatively modest, causing the loss of cell viability at concentrations in the mid-to-high micromolar range (18)(19)(20)(21)(22)(23)(24)(25).…”

Section: Significancementioning

confidence: 99%

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Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Risinger²,

Mitchell

et al. 2017

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

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Mass-spectrometry-based metabolomics and molecular phylogeny data were used to identify a metabolically prolific strain of Tolypocladium that was obtained from a deep-water Great Lakes sediment sample. An investigation of the isolate's secondary metabolome resulted in the purification of a 22-mer peptaibol, gichigamin A (1). This peptidic natural product exhibited an amino acid sequence including several β-alanines that occurred in a repeating ααβ motif, causing the compound to adopt a unique right-handed 3 11 helical structure. The unusual secondary structure of 1 was confirmed by spectroscopic approaches including solution NMR, electronic circular dichroism (ECD), and single-crystal X-ray diffraction analyses. Artificial and cell-based membrane permeability assays provided evidence that the unusual combination of structural features in gichigamins conferred on them an ability to penetrate the outer membranes of mammalian cells. Compound 1 exhibited potent in vitro cytotoxicity (GI 50 0.55 ± 0.04 μM) and in vivo antitumor effects in a MIA PaCa-2 xenograft mouse model. While the primary mechanism of cytotoxicity for 1 was consistent with ion leakage, we found that it was also able to directly depolarize mitochondria. Semisynthetic modification of 1 provided several analogs, including a C-terminus-linked coumarin derivative (22) that exhibited appreciably increased potency (GI 50 5.4 ± 0.1 nM), but lacked ion leakage capabilities associated with a majority of naturally occurring peptaibols such as alamethicin. Compound 22 was found to enter intact cells and induced cell death in a process that was preceded by mitochondrial depolarization.peptaibol | fungi | natural products | gichigamin | mitochondria N atural product chemical research has evolved in many extraordinary ways over the last decade largely due to the integration of powerful and accessible analytical chemistry (1, 2) and molecular biology (3, 4) tools. Some of these techniques have been applied toward the creation of natural product big-data sets in which genomic, metagenomic, metabolomic, and proteomic approaches are combined to obtain new insights into nature's remarkable chemical bounty (4-8). The predictive capabilities of these methods have helped guide efforts in several fertile areas of natural products research including the DNA cross-linking enediynes (9), bioactive cyanobacterial metabolites (10, 11), cytotoxic pentangular polyphenols (12), and thiopeptide antibiotics (13).The integration of analytical and molecular approaches is an effective way to find new natural product analogs that exhibit enhanced biological activities and improved pharmacological attributes (e.g., greater potency, better solubility, enhanced therapeutic index, etc.), but it also has the potential to uncover compounds with activities that are markedly dissimilar to other members of the queried chemical class. Nature is well known for its chemical repurposing capabilities, which allow populations of organisms to evolve new biological functions from existing molecular sc...

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Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Risinger²,

Mitchell

et al. 2017

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

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“…Alamethicins (ALMs) belong to a family of antibiotic peptides (peptaibols) of fungal origin that are known to selfassociate upon binding to lipid membranes (reviewed in (1)(2)(3)(4)(5)(6)(7)(8)). The most extensively studied isoform, ALM F50/5, is characterized by a linear sequence of 19 amino acids, eight of which are a-aminoisobutyric acid residues.…”

Section: Introductionmentioning

confidence: 99%

Alamethicin Supramolecular Organization in Lipid Membranes from 19F Solid-State NMR

Salnikov

Raya

Zotti

et al. 2016

Biophysical Journal

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Alamethicins (ALMs) are antimicrobial peptides of fungal origin. Their sequences are rich in hydrophobic amino acids and strongly interact with lipid membranes, where they cause a well-defined increase in conductivity. Therefore, the peptides are thought to form transmembrane helical bundles in which the more hydrophilic residues line a water-filled pore. Whereas the peptide has been well characterized in terms of secondary structure, membrane topology, and interactions, much fewer data are available regarding the quaternary arrangement of the helices within lipid bilayers. A new, to our knowledge, fluorine-labeled ALM derivative was prepared and characterized when reconstituted into phospholipid bilayers. As a part of these studies, C 19 F 3 -labeled compounds were characterized and calibrated for the first time, to our knowledge, for 19 F solid-state NMR distance and oligomerization measurements by centerband-only detection of exchange (CODEX) experiments, which opens up a large range of potential labeling schemes. The 19 F-19 F CODEX solid-state NMR experiments performed with ALM in POPC lipid bilayers and at peptide/lipid ratios of 1:13 are in excellent agreement with molecular-dynamics calculations of dynamic pentameric assemblies. When the peptide/lipid ratio was lowered to 1:30, ALM was found in the dimeric form, indicating that the supramolecular organization is tuned by equilibria that can be shifted by changes in environmental conditions.

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“…38 The mode of action of alamethicin is considered to be through its effect on biomembrane systems by ion channel formation in lipid-membranes bilayers. 17,39,40 It was reported that alamethicin seems to form ionic channels on chromaffin cells, which are permeable to Ca 2+ , Mn 2+ and Ni 2+ . 41 Dathe et al 42 reported that alamethicin induces catecholamine secretion from chromaffin cells and enhanced metabolic activity in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…50 We showed that antitrypanosomal activity of the peptide antibiotics discussed have cationic and lipophilic character in the structure (Figure 1) and also these antibiotics have any of the b-sheet, a-helical or loop conformations. 17,43,51 Therefore, these peptides might act more selectively on T. brucei than mammalian cells, in spite of their toxicity. In the case of leucinostatin A, it has been reported that leucinostatin A-loaded nanospheres show anti-Candida albicans activity both in vitro and in vivo, but with drastic reduction of toxicity.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo antitrypanosomal activities of three peptide antibiotics: leucinostatin A and B, alamethicin I and tsushimycin

et al. 2009

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In the course of our screening for antitrypanosomal compounds from soil microorganisms, as well as from the antibiotics library of the Kitasato Institute for Life Sciences, we found three peptide antibiotics, leucinostatin (A and B), alamethicin I and tsushimycin, which exhibited potent or moderate antitrypanosomal activity. We report here the in vitro and in vivo antitrypanosomal properties and cytotoxicities of leucinostatin A and B, alamethicin I and tsushimycin compared with suramin. We also discuss their possible mode of action. This is the first report of in vitro and in vivo trypanocidal activity of leucinostatin A and B, alamethicin I and tsushimycin.

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The History of Alamethicin: A Review of the Most Extensively Studied Peptaibol

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 40 publications

References 76 publications

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Alamethicin Supramolecular Organization in Lipid Membranes from 19F Solid-State NMR

In vitro and in vivo antitrypanosomal activities of three peptide antibiotics: leucinostatin A and B, alamethicin I and tsushimycin

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