Nature-derived peptide libraries for GPCR ligand discovery
Nature-derived peptide libraries for GPCR ligand discovery
Disciplines
Chemistry (20%); Medical-Theoretical Sciences, Pharmacy (80%)
Keywords
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Peptidomics,
Gpcr,
Peptide,
Drug Discovery,
Cyclotide
Bioactive peptides occur in all domains of life. Cyclotides are plant peptides comprising a circular backbone and three interlocked disulfide bonds that confer them with exceptional stability. This unique structure makes them interesting pharmaceutical tools for the development of orally bioavailable peptide-based drugs. Cyclotides exhibit several intrinsic biological activities, but the detailed molecular mechanisms of their effects have been studied in very few cases. For example, we have recently demonstrated that the cyclotide kalata B7 interacts with the human oxytocin and vasopressin V1a-receptors, belonging to the family of G protein-coupled receptors (GPCRs). These findings offer the unique opportunity to test whether cyclotides can target other GPCRs. Our scientific project aims to discover cyclotides and to use these nature-derived molecules as templates to design novel ligands for GPCRs; these transmembrane proteins constitute the most important class of therapeutic drug targets. To reach our objectives, we combine state-of-the-art pharmacological, chemical and bioanalytical approaches. If successful, these findings offer starting points for drug development of circular peptides to clinical relevant GPCRs.
Our project, entitled "Nature-derived peptides as libraries for GPCR ligand discovery," focuses on the exploration of circular peptides from plants to develop novel ligands for G protein-coupled receptors (GPCRs). This category of receptors is pivotal in therapeutic drug targeting. Our collaborative efforts blend advanced pharmacological, chemical, and bioanalytical methods. Significant progress includes establishing peptide-based GPCR ligands from diverse plant extracts and designing peptides that modulate the activity of key receptors like kappa-opioid and cannabinoid receptors. Notably, our research has led to the discovery of novel peptide ligands with potential therapeutic applications as analgesics or for autoimmune disorders, showcasing the immense potential of nature-derived molecules in medical science.
- David J. Craik, University of Queensland - Australia
- Liliane Schoofs, Katholieke Universiteit Leuven - Belgium
Research Output
- 3043 Citations
- 32 Publications
- 1 Patents
- 1 Spinouts
- 1 Methods & Materials
- 5 Disseminations
- 5 Scientific Awards
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2022
Title Ipecac root extracts and isolated circular peptides differentially suppress inflammatory immune response characterised by proliferation, activation and degranulation capacity of human lymphocytes in vitro DOI 10.5451/unibas-ep88523 Type Other Author Falanga -
2022
Title Multiplexed neuropeptide mapping in ant brains integrating microtomography and 3D mass spectrometry imaging DOI 10.1101/2022.11.02.514707 Type Preprint Author Geier B Pages 2022.11.02.514707 Link Publication -
2023
Title Peptide modulators of cell migration: Overview, applications and future development DOI 10.1016/j.drudis.2023.103554 Type Journal Article Author Gattringer J Journal Drug Discovery Today Pages 103554 Link Publication -
2023
Title Peptidomics DOI 10.1038/s43586-023-00205-2 Type Journal Article Author Hellinger R Journal Nature Reviews Methods Primers Pages 25 Link Publication -
2024
Title Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor DOI 10.1016/j.jbc.2024.107330 Type Journal Article Author Tomaševic N Journal Journal of Biological Chemistry Pages 107330 Link Publication -
2024
Title Chemical synthesis of grafted cyclotides using a “plug and play” approach DOI 10.1039/d4cb00008k Type Journal Article Author Koehbach J Journal RSC Chemical Biology Pages 567-571 Link Publication -
2022
Title Ipecac root extracts and isolated circular peptides differentially suppress inflammatory immune response characterised by proliferation, activation and degranulation capacity of human lymphocytes in vitro DOI 10.1016/j.biopha.2022.113120 Type Journal Article Author Falanga C Journal Biomedicine & Pharmacotherapy Pages 113120 Link Publication -
2022
Title Discovery of the cyclotide caripe 11 as a ligand of the cholecystokinin-2 receptor DOI 10.1038/s41598-022-13142-z Type Journal Article Author Taghizadeh M Journal Scientific Reports Pages 9215 Link Publication -
2023
Title Multiplexed neuropeptide mapping in ant brains integrating microtomography and three-dimensional mass spectrometry imaging DOI 10.1093/pnasnexus/pgad144 Type Journal Article Author Geier B Journal PNAS Nexus Link Publication -
2023
Title Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor DOI 10.1038/s41467-023-43718-w Type Journal Article Author Muratspahic E Journal Nature Communications Pages 8064 Link Publication -
2019
Title I8-arachnotocin–an arthropod-derived G protein-biased ligand of the human vasopressin V2 receptor DOI 10.1038/s41598-019-55675-w Type Journal Article Author Duerrauer L Journal Scientific Reports Pages 19295 Link Publication -
2019
Title Nature-Derived Peptides: A Growing Niche for GPCR Ligand Discovery DOI 10.1016/j.tips.2019.03.004 Type Journal Article Author Muratspahic E Journal Trends in Pharmacological Sciences Pages 309-326 Link Publication -
2024
Title Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists DOI 10.1021/acscentsci.3c01461 Type Journal Article Author Kosar M Journal ACS Central Science Pages 956-968 Link Publication -
2024
Title Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor DOI 10.26434/chemrxiv-2024-15qkc Type Preprint Author Tomasevic N Link Publication -
2024
Title Plant-Derived Peptides: (Neglected) Natural Products for Drug Discovery # DOI 10.1055/a-2219-9724 Type Journal Article Author Gruber C Journal Planta Medica Pages 627-630 Link Publication -
2023
Title Development of Melanocortin 4 Receptor Agonists by Exploiting Animal-Derived Macrocyclic, Disulfide-Rich Peptide Scaffolds DOI 10.1021/acsptsci.3c00090 Type Journal Article Author Muratspahic´ E Journal ACS Pharmacology & Translational Science Pages 1373-1381 Link Publication -
2023
Title Design, synthesis, conformational analysis, and biological activity of Ca1-to-Ca6 1,4- and 4,1-disubstituted 1H-[1,2,3]triazol-1-yl-bridged oxytocin analogues DOI 10.1080/14756366.2023.2254019 Type Journal Article Author Nuti F Journal Journal of Enzyme Inhibition and Medicinal Chemistry Pages 2254019 Link Publication -
2023
Title Development of a Selective Peptide ?-Opioid Receptor Antagonist by Late-Stage Functionalization with Cysteine Staples DOI 10.1021/acs.jmedchem.3c00426 Type Journal Article Author Muratspahic´ E Journal Journal of Medicinal Chemistry Pages 11843-11854 Link Publication -
2020
Title The oxytocin receptor signalling system and breast cancer: a critical review DOI 10.1038/s41388-020-01415-8 Type Journal Article Author Liu H Journal Oncogene Pages 5917-5932 Link Publication -
2021
Title Nature-inspired dimerization as a strategy to modulate neuropeptide pharmacology exemplified with vasopressin and oxytocin DOI 10.1039/d0sc05501h Type Journal Article Author Dekan Z Journal Chemical Science Pages 4057-4062 Link Publication -
2021
Title Natural products in drug discovery: advances and opportunities DOI 10.1038/s41573-020-00114-z Type Journal Article Author Atanasov A Journal Nature Reviews Drug Discovery Pages 200-216 Link Publication -
2021
Title Isolation and functional diversity of Bowman–Birk type serine proteinase inhibitors from Hyacinthus orientalis DOI 10.1042/bcj20201005 Type Journal Article Author Aoki-Shioi N Journal Biochemical Journal Pages 1287-1301 Link Publication -
2021
Title Cyclotides from Brazilian Palicourea sessilis and Their Effects on Human Lymphocytes DOI 10.1021/acs.jnatprod.0c01069 Type Journal Article Author Pinto M Journal Journal of Natural Products Pages 81-90 Link Publication -
2021
Title Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the ?-Opioid Receptor for the Treatment of Chronic Abdominal Pain DOI 10.1021/acs.jmedchem.1c00158 Type Journal Article Author Muratspahic´ E Journal Journal of Medicinal Chemistry Pages 9042-9055 Link Publication -
2021
Title Cyclotides Isolated From Violet Plants of Cameroon Are Inhibitors of Human Prolyl Oligopeptidase DOI 10.3389/fphar.2021.707596 Type Journal Article Author Gattringer J Journal Frontiers in Pharmacology Pages 707596 Link Publication -
2021
Title Plant-Derived Cyclotides Modulate ?-Opioid Receptor Signaling DOI 10.1021/acs.jnatprod.1c00301 Type Journal Article Author Muratspahic´ E Journal Journal of Natural Products Pages 2238-2248 Link Publication -
2020
Title Isolation of Cysteine-Rich Peptides from Citrullus colocynthis DOI 10.3390/biom10091326 Type Journal Article Author Shahin-Kaleybar B Journal Biomolecules Pages 1326 Link Publication -
2020
Title Discovery of a Beetroot Protease Inhibitor to Identify and Classify Plant-Derived Cystine Knot Peptides DOI 10.1021/acs.jnatprod.0c00648 Type Journal Article Author Retzl B Journal Journal of Natural Products Pages 3305-3314 Link Publication -
2020
Title Harnessing cyclotides to design and develop novel peptide GPCR ligands DOI 10.1039/d0cb00062k Type Journal Article Author Muratspahic E Journal RSC Chemical Biology Pages 177-191 Link Publication -
2021
Title Genome Mining-Based Discovery of Blenny Fish-Derived Peptides Targeting the Mouse ?-Opioid Receptor DOI 10.3389/fphar.2021.773029 Type Journal Article Author Muratspahic E Journal Frontiers in Pharmacology Pages 773029 Link Publication -
2021
Title Importance of the Cyclic Cystine Knot Structural Motif for Immunosuppressive Effects of Cyclotides DOI 10.1021/acschembio.1c00524 Type Journal Article Author Hellinger R Journal ACS Chemical Biology Pages 2373-2386 Link Publication -
2021
Title Discovery and design of cyclic nature-derived peptides targeting κ-opioid receptor Type PhD Thesis Author Edin Muratspahic
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2023
Title Selective cyclized peptide kappa-opioid receptor ligands Type Patent / Patent application Website Link
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2020
Title Press release MUW Type A press release, press conference or response to a media enquiry/interview -
2021
Title PRess release MUW Type A press release, press conference or response to a media enquiry/interview -
2023
Title Press release MUW Type A press release, press conference or response to a media enquiry/interview -
2023
Title Radio Interview, Science Podcast Type A press release, press conference or response to a media enquiry/interview -
2020
Title VHS Vortrag Type A talk or presentation
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2023
Title Best Poster Type Poster/abstract prize Level of Recognition National (any country) -
2022
Title Invited speaker Type Personally asked as a key note speaker to a conference Level of Recognition Continental/International -
2022
Title STMS Type Research prize Level of Recognition Continental/International -
2021
Title Editor Type Appointed as the editor/advisor to a journal or book series Level of Recognition Continental/International -
2019
Title Invited speaker Type Personally asked as a key note speaker to a conference Level of Recognition Continental/International