Anti-HIV cyclotides from the Chinese medicinal herb Viola yedoensis.
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ABSTRACT:
SUBMITTER: Wang CK
PROVIDER: S-EPMC6327322 | biostudies-literature | 2008 Jan
REPOSITORIES: biostudies-literature
Publications
Anti-HIV cyclotides from the Chinese medicinal herb Viola yedoensis.
Wang Conan K L CK Colgrave Michelle L ML Gustafson Kirk R KR Ireland David C DC Goransson Ulf U Craik David J DJ
Journal of natural products 20071215 1
Cyclotides are macrocyclic plant peptides characterized by a knotted arrangement of three disulfide bonds. They display a range of interesting bioactivities, including anti-HIV and insecticidal activities. More than 100 different cyclotides have been isolated from two phylogenetically distant plant families, the Rubiaceae and Violaceae. In this study we have characterized the cyclotides from Viola yedoensis, an important Chinese herb from the Violaceae family that has been reported to contain po ...[more]
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Project description:Cyclotides are disulfide rich macrocyclic plant peptides that are defined by their unique topology in which a head-to-tail cyclized backbone is knotted by the interlocking arrangement of three disulfide bonds. This cyclic cystine knot motif gives the cyclotides exceptional resistance to thermal, chemical, or enzymatic degradation. Over 100 cyclotides have been reported and display a variety of biological activities, including a cytoprotective effect against HIV infected cells. It has been hypothesized that cyclotides from one subfamily, the Möbius subfamily, may be more appropriate than bracelet cyclotides as drug candidates given their lower toxicity to uninfected cells. Here, we report the anti-HIV and cytotoxic effects of three cyclotides, including two from the Möbius subfamily. We show that Möbius cyclotides have comparable inhibitory activity against HIV infection to bracelet cyclotides and that they are generally less cytotoxic to the target cells. To explore the structure activity relationships (SARs) of the 29 cyclotides tested so far for anti-HIV activity, we modeled the structures of the 21 cyclotides whose structures have not been previously solved. We show that within cyclotide subfamilies there is a correlation between hydrophobicity of certain loop regions and HIV inhibition. We also show that charged residues in these loops impact on the activity of the cyclotides, presumably by modulating membrane binding. In addition to providing new SAR data, this report is a mini-review that collates all cyclotide anti-HIV information reported so far and provides a resource for future studies on the therapeutic potential of cyclotides as natural anti-HIV agents.
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Project description:Ethnopharmacological relevanceAccording to Traditional Chinese Medicine theory, influenza is categorized as a warm disease or Wen Bing. The Wen Bing formulas, such as Yin-Qiao-San and Sang-Ju-Yin, are still first-line herbal therapies in combating variant influenza virus. To continue our study on the pharmacokinetic and pharmacodynamic interactions between Wen Bing formulas and oseltamivir (OS), the first-line western drug for the treatment of influenza, further interactions between OS and the eight single herbs and their relevant marker components from Wen Bing formulas were investigated in the current study.Aim of studyTo establish an in-vitro screening platform for investigation of the potential anti-influenza herbs/herbal components that may have pharmacokinetic and pharmacodynamic interactions with OS.Materials and methodsTo screen potential inhibition on OS hydrolysis, 1 μg/mL of OS is incubated with herbs/herbal components in diluted rat plasma, microsomes and human recombinant carboxylesterase 1(hCE1) under optimized conditions. MDCK-WT and MDCK-MDR1 cell lines are utilized to identify potential modification on P-gp mediated transport of OS by herbs/herbal components. Caco-2 cells with and without Gly-Sar inhibition are performed to study the uptake of OS via PEPT1 transporters. Modification on OAT3 mediated transport is verified by the uptake of OS on HEK293-MOCK/HEK293-OAT3 cells. Anti-virus effects were evaluated using plaque reduction assay on H1N1 and H3N2 viruses. Potential pharmacokinetic and pharmacodynamic interaction between OS (30 mg/kg) and the selected herb, Radix Scutellariae (RS), at 300-600 mg/kg were carried out on rats. All samples are analyzed by an LC/MS/MS method for the contents of OS and OSA. A mechanistic PK model was developed to interpret the HDI between OS and RS in rats.ResultsOur developed platform was successfully applied to screen the eight herbal extracts and their ten marker components on metabolic inhibition of OS and modification of OS transport mediated by P-gp, OAT3 and PEPT1. Results from six in-vitro experiments were analyzed after converting raw data from each experiment to corresponding fold-change (FC) values, based on which Radix Scutellariae (RS) were selected to have the most HDI potential with OS. By analyzing the plasma and urine pharmacokinetic data after co-administration of OS with a standardized RS extract in rats using an integrated population pharmacokinetics model, it is suggested that RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which leads to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine. Never the less, the anti-virus effects of 2.5 h post-dose rat plasma were not influenced by co-administration of OS with RS.ConclusionA six-dimension in-vitro screening platform has been developed and successfully applied to find RS as a potential herb that would influence the co-administrated OS in rats. Although co-administered RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which lead to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine, the anti-virus effect of OS was not influenced by co-administered RS.
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Project description:Transcriptomic data from seven different tissues of Z. nitidum were collected to unveil the functional patterns of the BBE family in the biosynthesis of benzophenanthridine alkaloids
2024-11-10 | GSE281536 | GEO
Project description:Cyclotides are a family of plant-derived peptides characterized by a ~30 amino acid cyclic backbone and a cystine knot motif. Cyclotides have diverse bioactivities, and in particular their cytotoxicity has attracted significant attention for its potential anti-cancer applications. Hybanthus enneaspermus is a medicinal herb widely used in India as a natural libido enhancer, and a previous study indicated that it may contain cyclotides. In the current study, 11 novel cyclotides and one known cyclotide (cycloviolacin O2) were identified and isolated from H. enneaspermus. Their sequences were determined using tandem MS, and NMR analysis of six of these cyclotides indicates their three-dimensional structures are similar to those of other known cyclotides. The most abundant cyclotide in this plant, hyen D, has comparable cytotoxicity against cancer cells to cycloviolacin O2, the most cytotoxic cyclotide discovered so far. Herein we provide a mechanistic insight into the mode-of-action of the novel cyclotides’ cytotoxicity. Hyen D, E, L, M, and cycloviolacin O2 preferentially interacted with model lipid membranes containing phospholipids with phosphatidylethanolamine-headgroups, as measured by surface plasmon resonance. Cyclotide-membrane interactions correlated with cytotoxicity, suggesting that membrane binding underpins cytotoxicity. Overall, this study helps broaden knowledge on the indigenous Indian herb H. enneaspermus, and reports the discovery of novel cyclotides with potent anti-cancer activity.
2020-05-13 | PXD017924 | Pride
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