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Article ; Online: Peptide modulators of cell migration: Overview, applications and future development.

Gattringer, Jasmin / Gruber, Christian W / Hellinger, Roland

2023 Volume 28, Issue 5, Page(s) 103554

Abstract: Cell migration is a key physiological process in the development and homeostasis of multicellular organisms; errors in this complex system can trigger the development of cancer or inflammatory disorders. Therefore, modulating cell migration provides ... ...

Abstract	Cell migration is a key physiological process in the development and homeostasis of multicellular organisms; errors in this complex system can trigger the development of cancer or inflammatory disorders. Therefore, modulating cell migration provides opportunities for drug discovery. Peptides are gaining importance on the global therapeutics market, given their unique properties compared with established small-molecule drugs or biologics. In this review, we identified over 470 peptides modulating cell migration and analyzed their characteristics. Over 95% of these peptides are in the discovery or preclinical stage, because the transition of peptide hits into drug leads often results in a bottleneck in the development process. We summarize chemical strategies in (pre-)clinical development to enhance drug-like properties of bioactive peptides.
MeSH term(s)	Humans ; Peptides/pharmacology ; Peptides/therapeutic use ; Peptides/chemistry ; Neoplasms ; Cell Movement
Chemical Substances	Peptides
Language	English
Publishing date	2023-03-13
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1324988-5
ISSN	1878-5832 ; 1359-6446
ISSN (online)	1878-5832
ISSN	1359-6446
DOI	10.1016/j.drudis.2023.103554
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Article ; Online: Peptide-based protease inhibitors from plants.

Hellinger, Roland / Gruber, Christian W

Drug discovery today

2019 Volume 24, Issue 9, Page(s) 1877–1889

Abstract: 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- ... ...

Abstract	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.
MeSH term(s)	Humans ; Peptide Hydrolases/drug effects ; Plant Extracts ; Protease Inhibitors/chemistry ; Protease Inhibitors/classification
Chemical Substances	Plant Extracts ; Protease Inhibitors ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2019-06-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1324988-5
ISSN	1878-5832 ; 1359-6446
ISSN (online)	1878-5832
ISSN	1359-6446
DOI	10.1016/j.drudis.2019.05.026
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Article ; Online: Peptidomics.

Hellinger, Roland / Sigurdsson, Arnar / Wu, Wenxin / Romanova, Elena V / Li, Lingjun / Sweedler, Jonathan V / Süssmuth, Roderich D / Gruber, Christian W

Nature reviews. Methods primers

2023 Volume 3

Abstract: Peptides are biopolymers, typically consisting of 2-50 amino acids. They are biologically produced by the cellular ribosomal machinery or by non-ribosomal enzymes and, sometimes, other dedicated ligases. Peptides are arranged as linear chains or cycles, ... ...

Abstract	Peptides are biopolymers, typically consisting of 2-50 amino acids. They are biologically produced by the cellular ribosomal machinery or by non-ribosomal enzymes and, sometimes, other dedicated ligases. Peptides are arranged as linear chains or cycles, and include post-translational modifications, unusual amino acids and stabilizing motifs. Their structure and molecular size render them a unique chemical space, between small molecules and larger proteins. Peptides have important physiological functions as intrinsic signalling molecules, such as neuropeptides and peptide hormones, for cellular or interspecies communication, as toxins to catch prey or as defence molecules to fend off enemies and microorganisms. Clinically, they are gaining popularity as biomarkers or innovative therapeutics; to date there are more than 60 peptide drugs approved and more than 150 in clinical development. The emerging field of peptidomics comprises the comprehensive qualitative and quantitative analysis of the suite of peptides in a biological sample (endogenously produced, or exogenously administered as drugs). Peptidomics employs techniques of genomics, modern proteomics, state-of-the-art analytical chemistry and innovative computational biology, with a specialized set of tools. The complex biological matrices and often low abundance of analytes typically examined in peptidomics experiments require optimized sample preparation and isolation, including in silico analysis. This Primer covers the combination of techniques and workflows needed for peptide discovery and characterization and provides an overview of various biological and clinical applications of peptidomics.
Language	English
Publishing date	2023-05-30
Publishing country	England
Document type	Journal Article
ISSN	2662-8449
ISSN (online)	2662-8449
DOI	10.1038/s43586-023-00205-2
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Article ; Online: Multiplexed neuropeptide mapping in ant brains integrating microtomography and three-dimensional mass spectrometry imaging.

Geier, Benedikt / Gil-Mansilla, Esther / Liutkevičiūtė, Zita / Hellinger, Roland / Vanden Broeck, Jozef / Oetjen, Janina / Liebeke, Manuel / Gruber, Christian W

PNAS nexus

2023 Volume 2, Issue 5, Page(s) pgad144

Abstract: Neuropeptides are important regulators of animal physiology and behavior. Hitherto the gold standard for the localization of neuropeptides have been immunohistochemical methods that require the synthesis of antibody panels, while another limiting factor ... ...

Abstract	Neuropeptides are important regulators of animal physiology and behavior. Hitherto the gold standard for the localization of neuropeptides have been immunohistochemical methods that require the synthesis of antibody panels, while another limiting factor has been the brain's opacity for subsequent in situ light or fluorescence microscopy. To address these limitations, we explored the integration of high-resolution mass spectrometry imaging (MSI) with microtomography for a multiplexed mapping of neuropeptides in two evolutionary distant ant species,
Language	English
Publishing date	2023-04-25
Publishing country	England
Document type	Journal Article
ISSN	2752-6542
ISSN (online)	2752-6542
DOI	10.1093/pnasnexus/pgad144
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Article ; Online: Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor.

Tomašević, Nataša / Emser, Fabiola Susanna / Muratspahić, Edin / Gattringer, Jasmin / Hasinger, Simon / Hellinger, Roland / Keov, Peter / Felkl, Manuel / Gertsch, Jürg / Becker, Christian F W / Gruber, Christian W

The Journal of biological chemistry

2024 , Page(s) 107330

Abstract: The cannabinoid-type 2 receptor ( ... ...

Abstract	The cannabinoid-type 2 receptor (CB
Language	English
Publishing date	2024-04-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.107330
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Article: Cyclotides Isolated From Violet Plants of Cameroon Are Inhibitors of Human Prolyl Oligopeptidase.

Gattringer, Jasmin / Ndogo, Olivier Eteme / Retzl, Bernhard / Ebermann, Carina / Gruber, Christian W / Hellinger, Roland

Frontiers in pharmacology

2021 Volume 12, Page(s) 707596

Abstract: Traditional medicine and the use of herbal remedies are well established in the African health care system. For instance, Violaceae plants are used for antimicrobial or anti-inflammatory applications in folk medicine. This study describes the ... ...

Abstract	Traditional medicine and the use of herbal remedies are well established in the African health care system. For instance, Violaceae plants are used for antimicrobial or anti-inflammatory applications in folk medicine. This study describes the phytochemical analysis and bioactivity screening of four species of the violet
Language	English
Publishing date	2021-07-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.707596
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Article ; Online: Isolation and functional diversity of Bowman-Birk type serine proteinase inhibitors from Hyacinthus orientalis.

Aoki-Shioi, Narumi / Terada, Shigeyuki / Hellinger, Roland / Furuta, Yoshitaka / Gruber, Christian W

The Biochemical journal

2021 Volume 478, Issue 6, Page(s) 1287–1301

Abstract: Bowman-Birk inhibitors (BBIs) are plant-derived serine proteinase inhibitors. Endogenously, they function as defense molecules against pathogens and insects, but they also have been explored for applications in cancer treatment and inflammatory disorders. ...

Abstract	Bowman-Birk inhibitors (BBIs) are plant-derived serine proteinase inhibitors. Endogenously, they function as defense molecules against pathogens and insects, but they also have been explored for applications in cancer treatment and inflammatory disorders. Here, we isolated 15 novel BBIs from the bulb of Hyacinthus orientalis (termed HOSPIs). These isoinhibitors consisted of two or three chains, respectively, that are linked by disulfides bonds based on proposed cleavage sites in the canonical BBI reactive site loop. They strongly inhibited trypsin (Ki = 0.22-167 nM) and α-chymotrypsin (Ki = 19-1200 nM). Notably, HOSPI-B4 contains a six-residue reactive loop, which appears to be the smallest such motif discovered in BBIs to date. HOSPI-A6 and -A7 contain an unusual reactive site, i.e. Leu-Met at the P1-P1' position and have strong inhibitory activity against trypsin, α-chymotrypsin, and elastase. Analysis of the cDNA encoding HOSPIs revealed that the precursors have HOSPI-like domains repeated at least twice with a defined linker sequence connecting individual domains. Lastly, mutational analysis of HOSPIs suggested that the linker sequence does not affect the inhibitory activity, and a Thr residue at the P2 site and a Pro at the P3' site are crucial for elastase inhibition. Using mammalian proteases as representative model system, we gain novel insight into the sequence diversity and proteolytic activity of plant BBI. These results may aid the rational design of BBI peptides with potent and distinct inhibitory activity against human, pathogen, or insect serine proteinases.
MeSH term(s)	Amino Acid Sequence ; Cloning, Molecular ; Hyacinthus/enzymology ; Hyacinthus/genetics ; Sequence Homology ; Serine Proteinase Inhibitors/genetics ; Serine Proteinase Inhibitors/isolation & purification ; Serine Proteinase Inhibitors/pharmacology ; Substrate Specificity
Chemical Substances	Serine Proteinase Inhibitors
Language	English
Publishing date	2021-03-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20201005
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Article ; Online: Discovery of a Beetroot Protease Inhibitor to Identify and Classify Plant-Derived Cystine Knot Peptides.

Retzl, Bernhard / Hellinger, Roland / Muratspahić, Edin / Pinto, Meri E F / Bolzani, Vanderlan S / Gruber, Christian W

Journal of natural products

2020 Volume 83, Issue 11, Page(s) 3305–3314

Abstract: Plant peptide protease inhibitors are important molecules in seed storage metabolism and to fight insect pests. Commonly they contain multiple disulfide bonds and are exceptionally stable molecules. In this study, a novel peptide protease inhibitor from ... ...

Abstract	Plant peptide protease inhibitors are important molecules in seed storage metabolism and to fight insect pests. Commonly they contain multiple disulfide bonds and are exceptionally stable molecules. In this study, a novel peptide protease inhibitor from beetroot (
MeSH term(s)	Amino Acid Sequence ; Beta vulgaris/chemistry ; Cystine/chemistry ; Drug Discovery ; Peptides/chemistry ; Phylogeny ; Plant Proteins/chemistry ; Protease Inhibitors/pharmacology ; Proteolysis ; Sequence Homology, Amino Acid ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Chemical Substances	Peptides ; Plant Proteins ; Protease Inhibitors ; Cystine (48TCX9A1VT)
Language	English
Publishing date	2020-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.0c00648
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Article ; Online: Importance of the Cyclic Cystine Knot Structural Motif for Immunosuppressive Effects of Cyclotides.

Hellinger, Roland / Muratspahić, Edin / Devi, Seema / Koehbach, Johannes / Vasileva, Mina / Harvey, Peta J / Craik, David J / Gründemann, Carsten / Gruber, Christian W

ACS chemical biology

2021 Volume 16, Issue 11, Page(s) 2373–2386

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 ... ...

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.
MeSH term(s)	Cell Proliferation/drug effects ; Cyclotides/chemistry ; Cyclotides/metabolism ; Cyclotides/pharmacology ; Cystine Knot Motifs ; Humans ; Immunosuppressive Agents/metabolism ; Immunosuppressive Agents/pharmacology ; Monocytes/cytology ; Monocytes/drug effects ; Protein Conformation
Chemical Substances	Cyclotides ; Immunosuppressive Agents
Language	English
Publishing date	2021-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.1c00524
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Article: Discovery of a Beetroot Protease Inhibitor to Identify and Classify Plant-Derived Cystine Knot Peptides

Retzl, Bernhard / Hellinger, Roland / Muratspahić, Edin / Pinto, Meri E. F / Bolzani, Vanderlan S / Gruber, Christian W

Journal of natural products. 2020 Oct. 29, v. 83, no. 11

2020

Abstract	Plant peptide protease inhibitors are important molecules in seed storage metabolism and to fight insect pests. Commonly they contain multiple disulfide bonds and are exceptionally stable molecules. In this study, a novel peptide protease inhibitor from beetroot (Beta vulgaris) termed bevuTI-I was isolated, and its primary structure was determined via mass spectrometry-based amino acid sequencing. By sequence homology analysis a few peptides with high similarity to bevuTI-I, also known as the Mirabilis jalapa trypsin inhibitor subfamily of knottin-type protease inhibitors, were discovered. Hence, we assessed bevuTI-I for inhibitory activity toward trypsin (IC₅₀ = 471 nM) and human prolyl oligopeptidase (IC₅₀ = 11 μM), which is an emerging drug target for neurodegenerative and inflammatory disorders. Interestingly, using a customized bioinformatics approach, bevuTI-I was found to be the missing link to annotate 243 novel sequences of M. jalapa trypsin inhibitor-like peptides. According to their phylogenetic distribution they appear to be common in several plant families. Therefore, the presented approach and our results may help to discover and classify other plant-derived cystine knot peptides, a class of plant molecules that play important functions in plant physiology and are currently being explored as lead molecules and scaffolds in drug development.
Keywords	Beta vulgaris ; Mirabilis jalapa ; beets ; bioinformatics ; cystine ; drug development ; drugs ; humans ; mass spectrometry ; metabolism ; peptides ; phylogeny ; plant physiology ; prolyl oligopeptidase ; seed storage ; sequence homology ; trypsin ; trypsin inhibitors
Language	English
Dates of publication	2020-1029
Size	p. 3305-3314.
Publishing place	American Chemical Society and American Society of Pharmacognosy
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.0c00648
Database	NAL-Catalogue (AGRICOLA)

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