ArticleACS chemical biology2021
Importance of the Cyclic Cystine Knot Structural Motif for Immunosuppressive Effects of Cyclotides.
Article in ACS chemical biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 28 citations in OpenAlex.
- Molecular insights into anti-cancer cyclotides and their interaction with breast cancer targets: an in silico study.Molecular diversity · 2026Article
- Tangled Tail of Mechanically Interlocked Peptides.Journal of the American Chemical Society · 2026Review
- Tropical psychotria plants are a rich source for peptide inhibitors of human prolyl oligopeptidase.Natural products and bioprospecting · 2026Article
- Advances in cyclotide research: bioactivity to cyclotide-based therapeutics.Molecular diversity · 2025Review
- Small and Versatile Cyclotides as Anti-infective Agents.ACS infectious diseases · 2025Review
- Activation of the Calcium-Sensing Receptor by a Subfraction of Amino Acids Contained in Thyroid Drainage Fluid.ACS pharmacology & translational science · 2024Article
- Immunosuppressive Cyclotides: A Promising Approach for Treating Autoimmune Diseases.The protein journal · 2024Review
- Development and Challenges of Cyclic Peptides for Immunomodulation.Current protein & peptide science · 2024Review
- Exploring Immune Modulatory Effects of Cyclotide-Enriched Viola tricolor Preparations.Planta medica · 2023Article
- Design methods for antimicrobial peptides with improved performance.Zoological research · 2023Review
- Peptide modulators of cell migration: Overview, applications and future development.Drug discovery today · 2023Review
- Plant-based production of an orally active cyclotide for the treatment of multiple sclerosis.Transgenic research · 2023Article
- Peptidomics.Nature reviews. Methods primers · 2023Article
- Nutritional and Pharmaceutical Applications of Under-Explored Knottin Peptide-Rich Phytomedicines.Plants (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 4 countries.
Funding
Abstract
The cyclotide T20K inhibits the proliferation of human immune cells and is currently in clinical trials for multiple sclerosis. Here, we provide novel functional data and mechanistic insights into structure-activity relationships of T20K. Analogs with partial or complete reduction of the cystine knot had loss of function in proliferation experiments. Similarly, an acyclic analog of T20K was inactive in lymphocyte bioassays. The lack of activity of non-native peptide analogs appears to be associated with the ability of cyclotides to interact with and penetrate cell membranes, since cellular uptake studies demonstrated fast fractional transfer only of the native peptide into the cytosol of human immune cells. Therefore, structural differences between cyclic and linear native folded peptides were investigated by NMR to elucidate structure-activity relationships. Acyclic T20K had a less rigid backbone and considerable structural changes in loops 1 and 6 compared to the native cyclic T20K, supporting the idea that the cyclic cystine knot motif is a unique bioactive scaffold. This study provides evidence that this structural motif in cyclotides governs bioactivity, interactions with and transport across biological membranes, and the structural integrity of these peptides. These observations could be useful to understand the structure-activity of other cystine knot proteins due to the structural conservation of the cystine knot motif across evolution and to provide guidance for the design of novel cyclic cysteine-stabilized molecules.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.