T20K: An Immunomodulatory Cyclotide on Its Way to the Clinic

Gründemann, Carsten; Stenberg, Kjell G.; Gruber, Christian W.

doi:10.1007/s10989-018-9701-1

Cited by 51 publications

(58 citation statements)

References 24 publications

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“…In 2017, Sero-X, which is a cyclotide-based eco-friendly pesticide extracted from Clitoria ternatea (2), was approved to market in Australia for the protection of cotton and macadamia nut crops (https://innovateag.com.au/). In 2019, a single-residue mutated variant of cyclotide kalata B1, [T20K]kalata B1, entered Phase I clinical trials for multiple sclerosis (3). These examples foreshadow the great potential of cyclotides in both agriculture and medicine.…”

Section: Introductionmentioning

confidence: 99%

Discovery and mechanistic studies of cytotoxic cyclotides from the medicinal herb Hybanthus enneaspermus

Chan

Gilding

et al. 2020

Journal of Biological Chemistry

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Cyclotides are plant-derived peptides characterized by a ~30-amino-acid-long cyclic backbone and a cystine knot motif. Cyclotides have diverse bioactivities, and their cytotoxicity has attracted significant attention for its potential anticancer applications. Hybanthus enneaspermus (Linn) F. Muell is a medicinal herb widely used in India as a libido enhancer, and a previous study has reported that it may contain cyclotides. In the current study, we isolated 11 novel cyclotides and one known cyclotide (cycloviolacin O2) from H. enneaspermus and used tandem MS to determine their amino acid sequences. We found that among these cyclotides, hyen C comprises a unique sequence in loops 1, 2, 3, 4, and 6 compared with known cyclotides. The most abundant cyclotide in this plant, hyen D, had anticancer activity comparable to that of cycloviolacin O2, one of the most cytotoxic known cyclotides. We also provide mechanistic insights into how these novel cyclotides interact with and permeabilize cell membranes. Results from surface plasmon resonance experiments revealed that hyen D, E, L, M, and cycloviolacin O2 preferentially interact with model lipid membranes that contain phospholipids with phosphatidyl-ethanolamine headgroups. The results of a lactate dehydrogenase assay indicated that exposure to these cyclotides compromises cell membrane integrity. Using live-cell imaging, we show that hyen D induces rapid membrane blebbing and cell necrosis. Cyclotide–membrane interactions correlated with the observed cytotoxicity, suggesting that membrane permeabilization and disintegration underpin cyclotide cytotoxicity. These findings broaden our knowledge on the indigenous Indian herb H. enneaspermus and have uncovered cyclotides with potential anticancer activity.

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Section: Introductionmentioning

confidence: 99%

Discovery and mechanistic studies of cytotoxic cyclotides from the medicinal herb Hybanthus enneaspermus

Chan

Gilding

et al. 2020

Journal of Biological Chemistry

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“… 37 , 38 The immunosuppressive cyclotide, kalata B1 mutant [T20K], recently completed preclinical evaluation as a potential drug for multiple sclerosis (MS). 39 …”

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confidence: 99%

Cyclotides from Brazilian Palicourea sessilis and Their Effects on Human Lymphocytes

et al. 2021

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Cyclotides are plant-derived peptides found within five families of flowering plants (Violaceae, Rubiaceae, Fabaceae, Solanaceae, and Poaceae) that have a cyclic backbone and six conserved cysteine residues linked by disulfide bonds. Their presence within the Violaceae species seems ubiquitous, yet not all members of other families produce these macrocyclic peptides. The genus Palicourea Aubl. (Rubiaceae) contains hundreds of neotropical species of shrubs and small trees; however, only a few cyclotides have been discovered hitherto. Herein, five previously uncharacterized Möbius cyclotides within Palicourea sessilis and their pharmacological activities are described. Cyclotides were isolated from leaves and stems of this plant and identified as pase A–E, as well as the known peptide kalata S. Cyclotides were de novo sequenced by MALDI-TOF/TOF mass spectrometry, and their structures were solved by NMR spectroscopy. Because some cyclotides have been reported to modulate immune cells, pase A–D were assayed for cell proliferation of human primary activated T lymphocytes, and the results showed a dose-dependent antiproliferative function. The toxicity on other nonimmune cells was also assessed. This study reveals that pase cyclotides have potential for applications as immunosuppressants and in immune-related disorders.

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“…The observed therapeutic effect is promising, because the compound reduced the infiltration of encephalomyelitic cells into the spinal cord and the central nervous system, as well as the inflammatory response by Th 1 and Th 17 effector T cells [21]. Another plant PI, the cyclotide analog [T20 K]kalata B1, exhibited immunosuppressive effects in the EAE model in an IL-2-dependent mechanism [35,57,124].…”

Section: Plant Protease Inhibitors Target Human Disease Relevant Protmentioning

confidence: 99%

Peptide-based protease inhibitors from plants

Hellinger

Gruber

2019

Drug Discovery Today

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Proteases have an important role in homeostasis, and dysregulation of protease function can lead to pathogenesis. Therefore, proteases are promising drug targets in cancer, inflammation, and neurodegenerative disease research. Although there are well-established pharmaceuticals on the market, drug development for proteases is challenging. This is often caused by the limited selectivity of currently available lead compounds. Proteinaceous plant protease inhibitors are a diverse family of (poly)peptides that are important to maintain physiological homeostasis and to serve the innate defense machinery of the plant. In this review, we provide an overview of the diversity of plant peptide- and protein-based protease inhibitors (PIs), provide examples of such compounds that target human proteases, and discuss opportunities for these molecules in protease drug discovery and development.

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T20K: An Immunomodulatory Cyclotide on Its Way to the Clinic

Cited by 51 publications

References 24 publications

Discovery and mechanistic studies of cytotoxic cyclotides from the medicinal herb Hybanthus enneaspermus

Discovery and mechanistic studies of cytotoxic cyclotides from the medicinal herb Hybanthus enneaspermus

Cyclotides from Brazilian Palicourea sessilis and Their Effects on Human Lymphocytes

Peptide-based protease inhibitors from plants

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