Uterotonic Plants and their Bioactive Constituents

Gruber, Christian W.; O’Brien, Margaret

doi:10.1055/s-0030-1250317

Cited by 89 publications

(78 citation statements)

References 168 publications

(167 reference statements)

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“…Sequence analysis of kalata B7 showed high homology between its loop 3 (-CYTQGC-) and human oxytocin (CYIQNCPLG) ( Table S1). In humans, oxytocin acts on the oxytocin and vasopressin receptors and is one of the key players in the induction of labor and uterine contraction (20). Oxytocin and V 1a receptors are both expressed in the pregnant human uterus and are up-regulated during parturition, making the tissue more sensitive for stimulation (26).…”

Section: Discussionmentioning

confidence: 99%

“…Oxytocin and V 1a receptors are both expressed in the pregnant human uterus and are up-regulated during parturition, making the tissue more sensitive for stimulation (26). The endogenous ligand oxytocin is used clinically to induce labor and to prevent life-threatening postpartum bleeding (20). Kalata B7 is a partial agonist on uterine smooth muscle cells and cells expressing the human oxytocin and V 1a receptors (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…One physiological regulator of uterine contraction is the neuropeptide oxytocin. In uterine tissue, this peptide activates oxytocin and vasopressin V 1a receptors (19)(20)(21), two members of the G protein-coupled receptor (GPCR) family. GPCRs are Significance G protein-coupled receptors (GPCRs) are promising drug targets: >30% of the currently marketed drugs elicit their actions by binding to these transmembrane receptors.…”

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confidence: 99%

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Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design

Koehbach

O’Brien

Muttenthaler

et al. 2013

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

140

161

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Cyclotides are plant peptides comprising a circular backbone and three conserved disulfide bonds that confer them with exceptional stability. They were originally discovered in Oldenlandia affinis based on their use in traditional African medicine to accelerate labor. Recently, cyclotides have been identified in numerous plant species of the coffee, violet, cucurbit, pea, potato, and grass families. Their unique structural topology, high stability, and tolerance to sequence variation make them promising templates for the development of peptide-based pharmaceuticals. However, the mechanisms underlying their biological activities remain largely unknown; specifically, a receptor for a native cyclotide has not been reported hitherto. Using bioactivity-guided fractionation of an herbal peptide extract known to indigenous healers as "kalatakalata," the cyclotide kalata B7 was found to induce strong contractility on human uterine smooth muscle cells. Radioligand displacement and second messenger-based reporter assays confirmed the oxytocin and vasopressin V 1a receptors, members of the G proteincoupled receptor family, as molecular targets for this cyclotide. Furthermore, we show that cyclotides can serve as templates for the design of selective G protein-coupled receptor ligands by generating an oxytocin-like peptide with nanomolar affinity. This nonapeptide elicited dose-dependent contractions on human myometrium. These observations provide a proof of concept for the development of cyclotide-based peptide ligands.yclotides are head-to-tail cyclized plant peptides containing three conserved disulfide bonds in a knotted arrangement known as a cyclic cystine-knot motif (1). This confers them high stability (2) and presumably improves their oral bioactivity relative to their linear counterparts (3). They were first discovered in a decoction of Oldenlandia affinis DC. (Rubiaceae) leaves, an herbal remedy used in traditional African medicine during childbirth (4). The observed induction of labor and shortened delivery time were later studied on isolated rat and rabbit uteri and on human uterine strips (4, 5). The peptides responsible for the contractility effects (5) raised interest because they survived boiling, presumably as a result of their unique 3D structure, which was elucidated in 1995 (6). Since then, several plant species of the coffee (Rubiaceae) (7), violet (Violaceae) (8), legume (Fabaceae) (9), potato (Solanaceae) (10) and grass (Poaceae) families (11) have been identified to produce cyclotides. Currently, ∼300 sequences have been reported (12), and the predicted number of >50,000 cyclotides in Rubiaceae alone (7) suggests them to be one of the largest peptide classes within the plant kingdom. Their high intercysteine sequence variability and structural plasticity (13), together with intrinsic bioactivities, make them interesting templates for the development of novel pharmaceuticals (14).However, five decades after the discovery of cyclotides, there still is not any information about specific molecular targe...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design

Koehbach

O’Brien

Muttenthaler

et al. 2013

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

140

161

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“…Kalata B2 (net charge -1) is generally taken as the prototypic member of AHDPs in cylotides [23,27] and was first reported in the early 1970s when it was identified in Oldenlandia affinis of the Rubiaceae (Table 1), which is widely dispersed over tropical Africa and is also found in tropical Asia [56][57][58]. The peptide derives its name from the fact that it is a component of the uterotonic agent in a medicinal preparation, kalata-kalata [58,59], which is derived from O. affinis and is used in parts of Africa to accelerate child birth [60,61]. Several recent studies reported that kalata B2, along with kalata B13 (net charge -2; Tables 1 and 2), which is also derived from O. affinis, possessed potent anticancer activity.…”

Section: Ahdps From Cyclotidesmentioning

confidence: 99%

Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action

Harris¹,

Prabhu²,

Dennison³

et al. 2016

PPL

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Abstract:It is becoming increasingly clear that plants ranging across the plant kingdom produce anionic host defence peptides (AHDPs) with potent activity against a wide variety of human cancers cells. In general, this activity involves membrane partitioning by AHDPs, which leads to membranolysis and / or internalization to attack intracellular targets such as DNA. Several models have been proposed to describe these events including: the toroidal pore and Shai-Matsuzaki-Huang mechanisms but, in general, the mechanisms underpinning the membrane interactions and anticancer activity of these peptides are poorly understood. Plant AHDPs with anticancer activity can be conveniently discussed with reference to two groups: cyclotides, which possess cyclic molecules stabilized by cysteine knot motifs, and other ADHPs that adopt extended andhelical conformations. Here, we review research into the anticancer action of these two groups of peptides along with current understanding of the mechanisms underpinning this action.

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“…16 Since their discovery in the coffee family (Rubiaceae), cyclotides have been extensively studied in the violets (Violaceae) and have recently been found in legumes (Fabaceae). [17][18][19] Although there is an increasing effort to screen plants of different families for the occurrence and distribution of cyclotides, 20 we still lack information on the individual cyclotide content of single plant species, mainly due to difficulties associated with the analytical analysis and the identification of cyclotides. Cyclotides possess a wide range of biological activities, e.g., insecticidal, 21,22 nematocidal, 23,24 antifouling, 25 and anti-HIV 26,27 activities, as well as cytotoxicity to lymphoma cell lines.…”

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confidence: 99%

Do plant cyclotides have potential as immunosuppressant peptides?

Gründemann

Christian

Koehbach

et al. 2012

European Journal of Integrative Medicine

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Cyclotides are an abundant and diverse group of ribosomally synthesized plant peptides containing a cyclic cystine-knotted structure that confers them with remarkable stability. They are explored for their distribution in plants, although little is known about the individual peptide content of a single species. Therefore, we chemically analyzed the crude extract of the coffeefamily plant Oldenlandia affinis using a rapid peptidomics workflow utilizing nano-LC-MS, peptide reconstruct with database identification, and MS/MS automated sequence analysis to determine its cyclotide content. Biologically, cyclotides are mainly explored for applications in agriculture and drug design; here we report their growth-inhibiting effects on primary cells of the ASSOCIATED CONTENT Supporting InformationSupplemental figures: Structural alignment of kalata B1 and B2 ( Figure S1), determination of IC 50 for antiproliferative effect of kalata B1 on PBMC ( Figure S2), and effects of melittin on cell proliferation and cytotoxicity on PBMC ( Figure S3). Supplemental table: Comparison of IC 50 values for kalata B1 on various cellular test systems (Table S1). Supplemental files: LC-MS reconstruct of O. affinis cyclotides (file S1), O. affinis database search results following digests and LC-MS/MS analysis (file S2), and cyclotide quantification data (file S3). This material is available free of charge via the Internet at http://pubs.acs.org. Europe PMC Funders GroupAuthor Manuscript J Nat Prod. Author manuscript; available in PMC 2012 July 18. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts human immune system using biological and immunological end points in cell-based test systems. LC-MS quantification of the active O. affinis plant extract triggered the characterization of the antiproliferative activity of kalata B1, one of the most abundant cyclotides in this extract, on primary activated human lymphocytes. The effect has a defined concentration range and was not due to cytotoxicity, thus opening a new avenue to utilize native and synthetically optimized plant cyclotides for applications in immune-related disorders and as immunosuppressant peptides.The body's immune system is a powerful weapon against pathogens, but malfunctioning can cause an over-reactivity of this defense machinery and in some instances lead to autoimmune diseases such as rheumatoid arthritis (RA) or Crohn's disease. Immunosuppression, the targeted reduction of the activation or efficacy of the immune system, is an option for the treatment of these conditions. Because T-lymphocytes have the greatest impact during this defense response, most immunosuppressive medications aim to act on these cells. A representative is the drug cyclosporine A, a cyclic nonribosomal depsipeptide of fungal origin, which is the method of choice for severe cases of RA, 1,2 although it has many and sometimes severe side effects. 3Other naturally occurring circular peptides with potential pharmaceutical applications have been found in various organisms ...

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Uterotonic Plants and their Bioactive Constituents

Cited by 89 publications

References 168 publications

Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design

Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design

Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action

Do plant cyclotides have potential as immunosuppressant peptides?

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