ORCID Profile
0000-0003-1996-4646
Current Organisations
Universität Wien
,
University of Vienna
,
University of Queensland
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Proteins and Peptides | Medicinal and Biomolecular Chemistry | Biologically active molecules | Neurocognitive Patterns and Neural Networks | Natural Products Chemistry | Characterisation of Biological Macromolecules | Proteins and peptides | Biochemistry and Cell Biology | Psychology | Organic Chemical Synthesis | Biologically Active Molecules | Basic Pharmacology | Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology) | Medicinal and biomolecular chemistry | Receptors and Membrane Biology |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in Psychology and Cognitive Sciences | Expanding Knowledge in Technology
Related Links
Publications
Pharmacological applications of natural peptide libraries.
Publisher: Springer Science and Business Media LLC
Date: 09-2012
Correction: Chemical synthesis of human trefoil factor 1 (TFF1) and its homodimer provides novel insights into their mechanisms of action
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0CC90250K
Abstract: Correction for ‘Chemical synthesis of human trefoil factor 1 (TFF1) and its homodimer provides novel insights into their mechanisms of action’ by Nayara Braga Emidio et al. , Chem. Commun. , 2020, DOI: 10.1039/D0CC02321C.
Nanoparticle cellular uptake by dendritic wedge peptides: achieving single peptide facilitated delivery
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7NR03362A
Abstract: Optimizing the cargo carrying capacity and especially the cellular delivery efficiency of functionalized nanoparticles.
Trefoil Factor Family: Unresolved Questions and Clinical Perspectives
Publisher: Elsevier BV
Date: 05-2019
Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-12-2017
DOI: 10.1126/SCISIGNAL.AAN3398
Abstract: An oxytocin derivative that may not trigger adverse side effects has been generated.
The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions
Publisher: MDPI AG
Date: 04-04-2020
DOI: 10.3390/IJMS21072508
Abstract: TFF1 is a protective peptide of the Trefoil Factor Family (TFF), which is co-secreted with the mucin MUC5AC, gastrokine 2 (GKN2), and IgG Fc binding protein (FCGBP) from gastric surface mucous cells. Tff1-deficient mice obligatorily develop antropyloric adenoma and about 30% progress to carcinomas, indicating that Tff1 is a tumor suppressor. As a hallmark, TFF1 contains seven cysteine residues with three disulfide bonds stabilizing the conserved TFF domain. Here, we systematically investigated the molecular forms of TFF1 in the human gastric mucosa. TFF1 mainly occurs in an unusual monomeric form, but also as a homodimer. Furthermore, minor amounts of TFF1 form heterodimers with GKN2, FCGBP, and an unknown partner protein, respectively. TFF1 also binds to the mucin MUC6 in vitro, as shown by overlay assays with synthetic 125I-labeled TFF1 homodimer. The dominant presence of a monomeric form with a free thiol group at Cys-58 is in agreement with previous studies in Xenopus laevis and mouse. Cys-58 is likely highly reactive due to flanking acid residues (PPEEEC58EF) and might act as a scavenger for extracellular reactive oxygen/nitrogen species protecting the gastric mucosa from damage by oxidative stress, e.g., H2O2 generated by dual oxidase (DUOX).
Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
Publisher: Springer Science and Business Media LLC
Date: 30-01-2014
DOI: 10.1038/NCOMMS4165
Abstract: Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development. However, drugable receptors in the gut present an attractive niche for peptide therapeutics. Here we demonstrate, in a mouse model of chronic abdominal pain, that oxytocin receptors are significantly upregulated in nociceptors innervating the colon. Correspondingly, we develop chemical strategies to engineer non-reducible and therefore more stable oxytocin analogues. Chemoselective selenide macrocyclization yields stabilized analogues equipotent to native oxytocin. Ultra-high-field nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized structure in solution, in marked contrast to earlier X-ray crystallography studies. Finally, we show that these seleno-oxytocin analogues potently inhibit colonic nociceptors both in vitro and in vivo in mice with chronic visceral hypersensitivity. Our findings have potentially important implications for clinical use of oxytocin analogues and disulphide-rich peptides in general.
Synthesis and characterisation of new ditetrazole-ligands as more rigid building blocks of envisaged iron(II) spin-crossover coordination polymers
Publisher: Elsevier BV
Date: 05-2005
Heterodimeric Insecticidal Peptide Provides New Insights into the Molecular and Functional Diversity of Ant Venoms
Publisher: American Chemical Society (ACS)
Date: 06-10-2020
Two for the Price of One: Heterobivalent Ligand Design Targeting Two Binding Sites on Voltage-Gated Sodium Channels Slows Ligand Dissociation and Enhances Potency
Publisher: American Chemical Society (ACS)
Date: 20-10-2020
Structure-activity studies on alpha-conotoxins.
Publisher: Bentham Science Publishers Ltd.
Date: 12-2011
DOI: 10.2174/138161211798999384
Abstract: Conotoxins are small bioactive highly structured peptides from the venom of marine cone snails (genus Conus). Over the past 50 million years these molluscs have developed a complex venom cocktail for each species that is comprised of 100-2000 distinct cysteine- rich peptides for prey capture and defence. This review focuses on an important and well-studied class of conotoxins, the α- conotoxins. These α-conotoxins are potent and selective antagonists of various subtypes of the nicotinic acetylcholine receptors (nAChRs). Key structure-activity relationship studies are presented to illustrate the common motifs, structural features and pharmacophores that define this interesting peptide class. Additionally, their synthesis, chemical modifications, the development of more selective and stable analogues and their therapeutic potential are discussed.
Modulating Oxytocin Activity and Plasma Stability by Disulfide Bond Engineering
Publisher: American Chemical Society (ACS)
Date: 30-11-2010
DOI: 10.1021/JM100989W
Abstract: Disulfide bond engineering is an important approach to improve the metabolic half-life of cysteine-containing peptides. Eleven analogues of oxytocin were synthesized including disulfide bond replacements by thioether, selenylsulfide, diselenide, and ditelluride bridges, and their stabilities in human plasma and activity at the human oxytocin receptor were assessed. The cystathionine (K(i) = 1.5 nM, and EC₅₀ = 32 nM), selenylsulfide (K(i) = 0.29/0.72 nM, and EC₅₀ = 2.6/154 nM), diselenide (K(i) = 11.8 nM, and EC₅₀ = 18 nM), and ditelluride analogues (K(i) = 7.6 nM, and EC₅₀ = 27.3 nM) retained considerable affinity and functional potency as compared to oxytocin (K(i) = 0.79 nM, and EC₅₀ = 15 nM), while shortening the disulfide bridge abolished binding and functional activity. The mimetics showed a 1.5-3-fold enhancement of plasma stability as compared to oxytocin (t(½) = 12 h). By contrast, the all-D-oxytocin and head to tail cyclic oxytocin analogues, while significantly more stable with half-lives greater than 48 h, had little or no detectable binding or functional activity.
Photoswitchable Probes of Oxytocin and Vasopressin
Publisher: American Chemical Society (ACS)
Date: 19-10-2023
Lipid Bilayer Crossing—The Gate of Symmetry. Water-Soluble Phenylproline-Based Blood-Brain Barrier Shuttles
Publisher: American Chemical Society (ACS)
Date: 02-06-2015
DOI: 10.1021/JACS.5B02050
Abstract: Drug delivery to the brain can be achieved by various means, including blood-brain barrier (BBB) disruption, neurosurgical-based approaches, and molecular design. Recently, passive diffusion BBB shuttles have been developed to transport low-molecular-weight drug candidates to the brain which would not be able to cross unaided. The low water solubility of these BBB shuttles has, however, prevented them from becoming a mainstream tool to deliver cargos across membranes. Here, we describe the design, synthesis, physicochemical characterization, and BBB-transport properties of phenylproline tetrapeptides, (PhPro)4, an improved class of BBB shuttles that operates via passive diffusion. These PhPro-based BBB shuttles showed 3 orders of magnitude improvement in water solubility compared to the gold-standard (N-MePhe)4, while retaining very high transport values. Transport capacity was confirmed when two therapeutically relevant cargos, nipecotic acid and l-3,4-dihydroxyphenylalanine (i.e., l-DOPA), were attached to the shuttle. Additionally, we used the unique chiral and conformationally restricted character of the (PhPro)4 shuttle to probe its chiral interactions with the lipid bilayer of the BBB. We studied the transport properties of 16 (PhPro)4 stereoisomers using the parallel artificial membrane permeability assay and looked at differences in secondary structure. Most stereoisomers displayed excellent transport values, yet this study also revealed pairs of enantiomers with high enantiomeric discrimination and different secondary structure, where one enantiomer maintained its high transport values while the other had significantly lower values, thereby confirming that stereochemistry plays a significant role in passive diffusion. This could open the door to the design of chiral and membrane-specific shuttles with potential applications in cell labeling and oncology.
Evaluation of diverse peptidyl motifs for cellular delivery of semiconductor quantum dots
Publisher: Springer Science and Business Media LLC
Date: 04-06-2013
DOI: 10.1007/S00216-013-6982-2
Abstract: Cell-penetrating peptides (CPPs) have rapidly become a mainstay technology for facilitating the delivery of a wide variety of nanomaterials to cells and tissues. Currently, the library of CPPs to choose from is still limited, with the HIV TAT-derived motif still being the most used. Among the many materials routinely delivered by CPPs, nanoparticles are of particular interest for a plethora of labeling, imaging, sensing, diagnostic, and therapeutic applications. The development of nanoparticle-based technologies for many of these uses will require access to a much larger number of functional peptide motifs that can both facilitate cellular delivery of different types of nanoparticles to cells and be used interchangeably in the presence of other peptides and proteins on the same surface. Here, we evaluate the utility of four peptidyl motifs for their ability to facilitate delivery of luminescent semiconductor quantum dots (QDs) in a model cell culture system. We find that an LAH4 motif, derived from a membrane-inserting antimicrobial peptide, and a chimeric sequence that combines a sweet arrow peptide with a portion originating from the superoxide dismutase enzyme provide effective cellular delivery of QDs. Interestingly, a derivative of the latter sequence lacking just a methyl group was found to be quite inefficient, suggesting that even small changes can have significant functional outcomes. Delivery was effected using 1 h incubation with cells, and fluorescent counterstaining strongly suggests an endosomal uptake process that requires a critical minimum number or ratio of peptides to be displayed on the QD surface. Concomitant cytoviability testing showed that the QD-peptide conjugates are minimally cytotoxic in the model COS-1 cell line tested. Potential applications of these peptides in the context of cellular delivery of nanoparticles and a variety of other (bio)molecules are discussed.
Site-specific pK a determination of selenocysteine residues in selenovasopressin by using 77Se NMR spectroscopy
Publisher: Wiley
Date: 14-10-2011
Ligand-Based Peptide Design and Combinatorial Peptide Libraries to Target G Protein-Coupled Receptors
Publisher: Bentham Science Publishers Ltd.
Date: 09-2010
Selenopeptide chemistry
Publisher: Wiley
Date: 24-10-2008
DOI: 10.1002/PSC.1075
Abstract: This review focuses on the chemical aspects of the 21st proteinogenic amino acid, selenocysteine in peptides and proteins. It describes the physicochemical properties of selenium/sulfur and selenocysteine/cysteine based on comprehensive structural (X-ray, NMR, CD) and biological data, and illustrates why selenocysteine is considered the most conservative substitution of cysteine. The main focus lies on the synthetic methods on selenocysteine incorporation into peptides and proteins, including an overview of the selenocysteine building block syntheses for Boc- and Fmoc-SPPS. Selenocysteine-mediated reactions such as native chemical ligation and dehydroalanine formation are addressed towards peptide conjugation. Selenopeptides have very interesting and distinct properties which lead to a erse range of applications such as structural, functional and mechanistic probes, robust scaffolds, enzymatic reaction design, peptide conjugations and folding tools.
Development of a human vasopressin V1a-receptor antagonist from an evolutionary-related insect neuropeptide
Publisher: Springer Science and Business Media LLC
Date: 02-2017
DOI: 10.1038/SREP41002
Abstract: Characterisation of G protein-coupled receptors (GPCR) relies on the availability of a toolbox of ligands that selectively modulate different functional states of the receptors. To uncover such molecules, we explored a unique strategy for ligand discovery that takes advantage of the evolutionary conservation of the 600-million-year-old oxytocin/vasopressin signalling system. We isolated the insect oxytocin/vasopressin orthologue inotocin from the black garden ant ( Lasius niger ), identified and cloned its cognate receptor and determined its pharmacological properties on the insect and human oxytocin/vasopressin receptors. Subsequently, we identified a functional dichotomy: inotocin activated the insect inotocin and the human vasopressin V 1b receptors, but inhibited the human V 1a R. Replacement of Arg8 of inotocin by D-Arg8 led to a potent, stable and competitive V 1a R-antagonist ([D-Arg8]-inotocin) with a 3,000-fold binding selectivity for the human V 1a R over the other three subtypes, OTR, V 1b R and V 2 R. The Arg8/D-Arg8 ligand-pair was further investigated to gain novel insights into the oxytocin/vasopressin peptide-receptor interaction, which led to the identification of key residues of the receptors that are important for ligand functionality and selectivity. These observations could play an important role for development of oxytocin/vasopressin receptor modulators that would enable clear distinction of the physiological and pathological responses of the in idual receptor subtypes.
Chemical synthesis of human trefoil factor 1 (TFF1) and its homodimer provides novel insights into their mechanisms of action
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0CC02321C
Abstract: Chemical synthesis of gut peptide TFF1 and its homodimer was achieved by a two-fragment ligation strategy followed by oxidative folding.
On-resin strategy to label α-Conotoxins: Cy5-RgIA, a Potent α9α10 nicotinic acetylcholine receptor imaging probe
Publisher: CSIRO Publishing
Date: 2020
DOI: 10.1071/CH19456
Abstract: In-solution conjugation is the most commonly used strategy to label peptides and proteins with fluorophores. However, lack of site-specific control and high costs of fluorophores are recognised limitations of this approach. Here, we established facile access to grams of Cy5-COOH via a two-step synthetic route, demonstrated that Cy5 is stable to HF treatment and therefore compatible with tert-butyloxycarbonyl solid phase peptide synthesis (Boc-SPPS), and coupled Cy5 to the N-terminus of α-conotoxin RgIA while still attached to the resin. Folding of the two-disulfide containing Cy5-RgIA benefitted from the hydrophobic nature of Cy5, resulting in only the globular disulfide bond isomer. In contrast, wild-type α-RgIA folded into the inactive ribbon and bioactive globular isomer under the same conditions. Labelled α-RgIA retained its ability to inhibit acetylcholine (100µM)-evoked current reversibly with an IC50 of 5.0nM (Hill coefficient=1.7) for Cy5-RgIA and an IC50 of 1.6 (Hill coefficient=1.2) for α-RgIA at the α9α10 nicotinic acetylcholine receptor (nAChR) heterologously expressed in Xenopus oocytes. Cy5-RgIA was then used to successfully visualise nAChRs in the RAW264.7 mouse macrophage cell line. This work introduced not only a new and valuable nAChR probe, but also a new versatile synthetic strategy that facilitates production of milligram to gram quantities of fluorophore-labelled peptides at low cost, which is often required for invivo experiments. The strategy is compatible with Boc- and 9-fluorenylmethoxycarbonyl (Fmoc)-chemistry, allows site-specific labelling of free amines anywhere in the peptide sequence, and can also be used for the introduction of Cy3/Cy5 fluorescence resonance energy transfer (FRET) pairs.
Discovery, synthesis, and structure-activity relationships of conotoxins
Publisher: American Chemical Society (ACS)
Date: 10-04-2014
DOI: 10.1021/CR400401E
Improving the Gastrointestinal Stability of Linaclotide
Publisher: American Chemical Society (ACS)
Date: 12-05-2021
Selenocystine Peptides – Synthesis, Folding and Applications
Publisher: The Royal Society of Chemistry
Date: 10-12-2009
On the Utility of Chemical Strategies to Improve Peptide Gut Stability
Publisher: American Chemical Society (ACS)
Date: 14-04-2022
Expanding the versatility and scope of the oxime ligation: rapid bioconjugation to disulfide-rich peptides
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2CC03752A
Abstract: Regiospecific incorporation of a protected aminooxy group into disulfide-rich peptides compatible with oxidative folding. This strategy supports the production of aminooxy precursors for long-term storage and on-demand modifications.
High Oxytocin Receptor Expression Linked to Increased Cell Migration and Reduced Survival in Patients with Triple-Negative Breast Cancer
Publisher: MDPI AG
Date: 05-07-2022
DOI: 10.3390/BIOMEDICINES10071595
Abstract: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options and high mortality. The oxytocin receptor (OTR) is a class-A G protein-coupled receptor that has been linked to breast cancer, but its role in tumorigenesis and disease progression remains underexplored. OTR expression is highest in tumour-adjacent breast tissue, followed by normal and tumour tissue, indicating a potential role in the tumour microenvironment. OTR levels were higher in migrated MDA-MB-231 cells than in the control parental cells cultured in normal medium OTR overexpression/knock-down and metastasis biomarker experiments revealed that high OTR expression enhanced metastasis capabilities. These findings align well with data from a murine breast cancer metastasis model, where metastasised tumours had higher OTR expression than the corresponding primary tumours, and high OTR expression also correlates to reduced survival in TNBC patients. OTR agonists/antagonists did not affect MDA-MB-231 cell migration, and pharmacological analysis revealed that the OT/OTR signalling was compromised. High OTR expression enhanced cell migration in an OTR ligand-independent manner, with the underlying mechanism linked to the EGF-mediated ERK1/2-RSK-rpS6 pathway. Taken together, high OTR expression seems to be involved in TNBC metastasis via increasing cell sensitivity to EGF. These results support a potential prognostic biomarker role of OTR and provide new mechanistic insights and opportunities for targeted treatment options for TNBC.
Anhydrous hydrogen fluoride cleavage in boc solid phase peptide synthesis
Publisher: Springer US
Date: 27-12-2020
Advancing the Frontiers of Chemical Protein Synthesis—The 7th CPS Meeting, Haifa, Israel
Publisher: Elsevier BV
Date: 03-2018
Nature-inspired dimerization as a strategy to modulate neuropeptide pharmacology exemplified with vasopressin and oxytocin
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0SC05501H
Abstract: Structural and pharmacological study of parallel, antiparallel and N- to C-terminal cyclized homo- and heterodimers of vasopressin and oxytocin. This study spotlights dimerization as a strategy to modulate the pharmacology of neuropeptides.
α-conotoxin AuIB isomers exhibit distinct inhibitory mechanisms and differential sensitivity to stoichiometry of α3β4 nicotinic acetylcholine receptors
Publisher: Elsevier BV
Date: 07-2010
Fmoc Solid Phase Peptide Synthesis of Oxytocin and Analogues
Publisher: Springer US
Date: 23-09-2021
Insights into the molecular evolution of oxytocin receptor ligand binding
Publisher: Portland Press Ltd.
Date: 29-01-2013
DOI: 10.1042/BST20120256
Abstract: The design and development of selective ligands for the human OT (oxytocin) and AVP (arginine vasopressin) receptors is a big challenge since the different receptor subtypes and their native peptide ligands display great similarity. Detailed understanding of the mechanism of OT's interaction with its receptor is important and may assist in the ligand- or structure-based design of selective and potent ligands. In the present article, we compared 69 OT- and OT-like receptor sequences with regards to their molecular evolution and ersity, utilized an in silico approach to map the common ligand interaction sites of recently published G-protein-coupled receptor structures to a model of the human OTR (OT receptor) and compared these interacting residues within a selection of different OTR sequences. Our analysis suggests the existence of a binding site for OT peptides within the common transmembrane core region of the receptor, but it appears extremely difficult to identify receptor or ligand residues that could explain the selectivity of OT to its receptors. We remain confident that the presented evolutionary overview and modelling approach will aid interpretation of forthcoming OTR crystal structures.
Discovery of Defense- and Neuropeptides in Social Ants by Genome-Mining
Publisher: Public Library of Science (PLoS)
Date: 20-03-2012
Approaches to Improve the Quantitation of Oxytocin in Human Serum by Mass Spectrometry
Publisher: Frontiers Media SA
Date: 09-06-2022
DOI: 10.3389/FCHEM.2022.889154
Abstract: The neuropeptide oxytocin (OT) regulates several peripheral and central functions and is a molecule of interest in psychiatric diseases such as autism spectrum disorder, schizophrenia, anxiety and depression. The study of OT in human serum s les is however h ered by inconsistent s le preparation and analysis as well as low endogenous blood concentration (1–10 pM). This results in varying reports on OT’s blood levels and interpretation of OT’s role in different (patho)physiological states. Quantitative mass spectrometry (MS) is a highly promising technology to address this problem but still requires large s le volumes to achieve adequate sensitivity and reliability for the quantitation of compounds at low concentrations. We therefore systematically evaluated s le preparation methods for MS to achieve a reliable s le preparation protocol with good peptide recovery, minimal matrix effects and good overall method efficiency in line with FDA guidelines for bioanalytic method development and validation. Additionally, we investigated a strategy to improve the ionization efficiency of OT by adding charged and/or hydrophobic moieties to OT to improve the lower limit of quantitation. Optimized s le preparation in combination with OT modification with a quaternary pyridinium ion improved the sensitivity of OT by ∼40-fold on a tandem triple quadrupole mass spectrometer (API4000 QTRAP), resulting in a lower limit of quantitation of 5 pM in water (linear range 5 pM – 1 mM) and 2 nM in human serum (linear range 2 nM – 1 mM) compared to 200 pM in water and 86 nM in serum with unmodified OT. This approach and protocol provide a solid foundation towards method development for OT quantitation using MS, which should be of high value for fundamental research as well as clinical monitoring of OT upon drug treatments.
Selected defense- and neuropeptides from ant species characterized by genome-mining.
Publisher: Public Library of Science (PLoS)
Date: 2012
Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design
Publisher: Proceedings of the National Academy of Sciences
Date: 18-11-2013
Abstract: G protein-coupled receptors (GPCRs) are promising drug targets: % of the currently marketed drugs elicit their actions by binding to these transmembrane receptors. However, only ∼10% of all GPCRs are targeted by approved drugs. Resorting to plant-derived compounds catalogued by ethnopharmacological analyses may increase this repertoire. We provide a proof of concept by analyzing the uterotonic action of an herbal remedy used in traditional African medicine. We identified cyclic peptides, investigated the molecular mechanisms underlying their uterotonic activity, and report an oxytocic plant peptide that modulates the human oxytocin/vasopressin receptors. This naturally occurring peptide served as a template for the design of an oxytocin-like nonapeptide with enhanced receptor selectivity, highlighting the potential of cyclotides for the discovery of peptide-based GPCR ligands.
Neuropeptide signalling systems -an underexplored target for venom drug discovery.
Publisher: Elsevier BV
Date: 11-2020
Conotoxins: Chemistry and Biology
Publisher: American Chemical Society (ACS)
Date: 21-10-2019
DOI: 10.1021/ACS.CHEMREV.9B00207
Abstract: The venom of the marine predatory cone snails (genus
Methods, setup and safe handling for anhydrous hydrogen fluoride cleavage in Boc solid-phase peptide synthesis
Publisher: Springer Science and Business Media LLC
Date: 18-06-2015
Abstract: Solid-phase peptide synthesis (SPPS) using tert-butyloxycarbonyl (Boc)/benzyl (Bzl) chemistry is an indispensable technique in many laboratories around the globe, and it provides peptides to the pharmaceutical industry and to thousands of scientists working in basic research. The Boc/Bzl strategy has several advantages, including reliability in the synthesis of long and difficult polypeptides, alternative orthogonality regarding protecting groups and ease of producing C-terminal thioesters for native chemical ligation applications. In this process, anhydrous hydrogen fluoride (HF) is used to remove the side chain protecting groups of the assembled peptide and to release the peptide from the resin, a process typically described as 'HF cleavage'. This protocol describes the general methodology, apparatus setup and safe handling of HF, with the aim of providing comprehensive information on the safe use of this valuable, well-studied and validated cleavage technique. We explain the cleavage mechanism, the physicochemical properties and risks of HF, first aid measures and the correct use of the apparatus. In addition, we provide advice on scavenger selection, as well as a troubleshooting section and video material illustrating key steps of the procedure. The protocol comprises precleavage s le preparation (30 min-2.5 h), complete HF cleavage procedure (2 h) and reaction workup (30 min).
Chemical Synthesis of TFF3 Reveals Novel Mechanistic Insights and a Gut-Stable Metabolite
Publisher: American Chemical Society (ACS)
Date: 18-06-2021
Solving the α-conotoxin folding problem: Efficient selenium-directed on-resin generation of more potent and stable nicotinic acetylcholine receptor antaqonists
Publisher: American Chemical Society (ACS)
Date: 17-02-2010
DOI: 10.1021/JA910602H
Abstract: Alpha-conotoxins are tightly folded miniproteins that antagonize nicotinic acetylcholine receptors (nAChR) with high specificity for erse subtypes. Here we report the use of selenocysteine in a supported phase method to direct native folding and produce alpha-conotoxins efficiently with improved biophysical properties. By replacing complementary cysteine pairs with selenocysteine pairs on an hiphilic resin, we were able to chemically direct all five structural subclasses of alpha-conotoxins exclusively into their native folds. X-ray analysis at 1.4 A resolution of alpha-selenoconotoxin PnIA confirmed the isosteric character of the diselenide bond and the integrity of the alpha-conotoxin fold. The alpha-selenoconotoxins exhibited similar or improved potency at rat diaphragm muscle and alpha3beta4, alpha7, and alpha1beta1 deltagamma nAChRs expressed in Xenopus oocytes plus improved disulfide bond scrambling stability in plasma. Together, these results underpin the development of more stable and potent nicotinic antagonists suitable for new drug therapies, and highlight the application of selenocysteine technology more broadly to disulfide-bonded peptides and proteins.
Peptide-mediated cellular delivery of semiconductor quantum dots
Publisher: SPIE
Date: 29-05-2013
DOI: 10.1117/12.2015446
I8-arachnotocin–an arthropod-derived G protein-biased ligand of the human vasopressin V2 receptor
Publisher: Springer Science and Business Media LLC
Date: 17-12-2019
DOI: 10.1038/S41598-019-55675-W
Abstract: The neuropeptides oxytocin (OT) and vasopressin (VP) and their G protein-coupled receptors OTR, V 1a R, V 1b R, and V 2 R form an important and widely-distributed neuroendocrine signaling system. In mammals, this signaling system regulates water homeostasis, blood pressure, reproduction, as well as social behaviors such as pair bonding, trust and aggression. There exists high demand for ligands with differing pharmacological profiles to study the physiological and pathological functions of the in idual receptor subtypes. Here, we present the pharmacological characterization of an arthropod ( Metaseiulus occidentalis ) OT/VP-like nonapeptide across the human OT/VP receptors. I8-arachnotocin is a full agonist with respect to second messenger signaling at human V 2 R (EC 50 34 nM) and V 1b R (EC 50 1.2 µM), a partial agonist at OTR (EC 50 790 nM), and a competitive antagonist at V 1a R [pA 2 6.25 (558 nM)]. Intriguingly, I8-arachnotocin activated the Gα s pathway of V 2 R without recruiting either β-arrestin-1 or β-arrestin-2. I8-arachnotocin might thus be a novel pharmacological tool to study the (patho)physiological relevance of β-arrestin-1 or -2 recruitment to the V 2 R. These findings furthermore highlight arthropods as a novel, vast and untapped source for the discovery of novel pharmacological probes and potential drug leads targeting neurohormone receptors.
Trends in peptide drug discovery
Publisher: Springer Science and Business Media LLC
Date: 03-02-2021
DOI: 10.1038/S41573-020-00135-8
Abstract: Since the introduction of insulin almost a century ago, more than 80 peptide drugs have reached the market for a wide range of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection and chronic pain. In this Perspective, we summarize key trends in peptide drug discovery and development, covering the early efforts focused on human hormones, elegant medicinal chemistry and rational design strategies, peptide drugs derived from nature, and major breakthroughs in molecular biology and peptide chemistry that continue to advance the field. We emphasize lessons from earlier approaches that are still relevant today as well as emerging strategies such as integrated venomics and peptide-display libraries that create new avenues for peptide drug discovery. We also discuss the pharmaceutical landscape in which peptide drugs could be particularly valuable and analyse the challenges that need to be addressed for them to reach their full potential.
Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract
Publisher: American Chemical Society (ACS)
Date: 09-06-2020
Evaluation of Chemical Strategies for Improving the Stability and Oral Toxicity of Insecticidal Peptides
Publisher: MDPI AG
Date: 28-08-2018
DOI: 10.3390/BIOMEDICINES6030090
Abstract: Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been h ered due to concerns about potential lack of stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies to increase the stability and oral potency of the potent insecticidal spider-venom peptide ω-HXTX-Hv1a (Hv1a). Selective chemical replacement of disulfide bridges with diselenide bonds and N- to C-terminal cyclization were anticipated to improve Hv1a resistance to proteolytic digestion, and thereby its activity when delivered orally. We found that native Hv1a is orally active in blowflies, but 91-fold less potent than when administered by injection. Introduction of a single diselenide bond had no effect on the susceptibility to scrambling or the oral activity of Hv1a. N- to C-terminal cyclization of the peptide backbone did not significantly improve the potency of Hv1a when injected into blowflies and it led to a significant decrease in oral activity. We show that this is likely due to a dramatically reduced rate of translocation of cyclic Hv1a across the insect midgut, highlighting the importance of testing bioavailability in addition to toxin stability.
The oxytocin receptor signalling system and breast cancer: a critical review
Publisher: Springer Science and Business Media LLC
Date: 11-08-2020
DOI: 10.1038/S41388-020-01415-8
Abstract: Breast cancer is making up one-quarter of all new female cancer cases diagnosed worldwide. Breast cancer surgeries, radiation therapies, cytotoxic chemotherapies and targeted therapies have made significant progress and play a dominant role in breast cancer patient management. However, many challenges remain, including resistance to systemic therapies, tumour recurrence and metastasis. The cyclic neuropeptide oxytocin (OT) elicits a plethora of biological responses via the oxytocin receptor (OTR) in both the central and peripheral nervous system, including social bonding, stress, maternal behaviour, sexual activity, uterus contraction, milk ejection and cancer. As a typical member of the G protein-coupled receptor family, OTR represents also an intriguing target for cancer therapy. There is emerging evidence that OTR plays a role in breast cancer development and progression, and several breast cancer cell lines express OTR. However, despite supporting evidence that OT lowers breast cancer risks, its mechanistic role in breast cancer development and the related signalling pathways are not fully understood. Here, we review the current knowledge of the OT/OTR signalling system in healthy breast tissue as well as in breast cancer, and discuss OTR as a potential therapeutic target for breast cancer management.
Oxytocin‐like signaling in ants influences metabolic gene expression and locomotor activity
Publisher: Wiley
Date: 25-06-2018
DOI: 10.1096/FJ.201800443
Synthesis of Multivalent [Lys(8)]-Oxytocin Dendrimers that Inhibit Visceral Nociceptive Responses
Publisher: CSIRO Publishing
Date: 2017
DOI: 10.1071/CH16407
Abstract: Peptide dendrimers are a novel class of precisely defined macromolecules of emerging interest. Here, we describe the synthesis, structure, binding affinity, receptor selectivity, functional activity, and antinociceptive properties of oxytocin-related dendrimers containing up to 16 copies of [Lys8]-oxytocin or LVT. These were generated using a copper(i)-catalyzed azide–alkyne cycloaddition (CuAAc) reaction with azido-pegylated LVT peptides on an alkyne–polylysine scaffold. 2D NMR analysis demonstrated that each attached LVT ligand was freely rotating and maintained identical 3D structures in each dendrimeric macromolecule. The binding affinity Ki at the oxytocin receptor increased approximately 17-, 12-, 3-, and 1.5-fold respectively for the 2-, 4-, 8-, and 16-mer dendrimeric LVT conjugates, compared with monomer azido-pegylated LVT (Ki = 9.5 nM), consistent with a multivalency effect. A similar trend in affinity was also observed at the related human V1a, V1b, and V2 receptors, with no significant selectivity change observed across this family of receptors. All LVT dendrimers were functionally active in vitro on human oxytocin receptors and inhibited colonic nociceptors potently in a mouse model of chronic abdominal pain.
Conopressin-T from Conus tulipa reveals an antagonist switch in vasopressin-like peptides
Publisher: Elsevier BV
Date: 03-2008
Exploring bioactive peptides from natural sources for oxytocin and vasopressin drug discovery
Publisher: Future Science Ltd
Date: 09-2012
DOI: 10.4155/FMC.12.108
Heterodimeric insecticidal peptide provides new insights into the molecular and functional diversity of ant venoms
Publisher: Cold Spring Harbor Laboratory
Date: 30-07-2020
DOI: 10.1101/2020.07.29.226878
Abstract: Ants use venom for predation, defence and communication, however, the molecular ersity, function and potential applications of ant venom remains understudied compared to other venomous lineages such as arachnids, snakes and cone snails. In this work, we used a multidisciplinary approach that encompassed field work, proteomics, sequencing, chemical synthesis, structural analysis, molecular modelling, stability studies, and a series of in vitro and in vivo bioassays to investigate the molecular ersity of the venom of the Amazonian Pseudomyrmex penetrator ants. We isolated a potent insecticidal heterodimeric peptide Δ-pseudomyrmecitoxin-Pp1a (Δ-PSDTX-Pp1a) composed of a 27-residue long A-chain and a 33-residue long B-chain crosslinked by two disulfide bonds in an antiparallel orientation. We chemically synthesised Δ-PSDTX-Pp1a, its corresponding parallel AA and BB homodimers, and its monomeric chains and demonstrated that Δ-PSDTX-Pp1a had the most potent insecticidal effects in blow fly assays (LD 50 = 3 nM). Molecular modelling and circular dichroism studies revealed strong alpha-helical features, indicating its cytotoxic effects could derive from membrane disruption, which was further supported by insect cell calcium assays. The native heterodimer was also substantially more stable against proteolytic degradation (t 1/2 =13 h) than its homodimers or monomers (t 1/2 min), indicating an evolutionary advantage of the more complex structure. The proteomic analysis of Pseudomyrmex penetrator venom and in-depth characterisation of Δ-PSDTX-Pp1a provide novel insights in the structural complexity of ant venom, and further exemplifies how nature exploits disulfide-bond formation and dimerization to gain an evolutionary advantage via improved stability a concept that is also highly relevant for the design and development of peptide therapeutics, molecular probes and bioinsecticides.
Conformational selection of vasopressin upon V1a receptor binding
Publisher: Elsevier BV
Date: 2021
p‐Nitrobenzyl protection for cysteine and selenocysteine: A more stable alternative to the acetamidomethyl group
Publisher: Wiley
Date: 2010
DOI: 10.1002/BIP.21502
Abstract: This study evaluated the acidic lability of the acetamidomethyl (Acm), trimethylacetamidomethyl (Tacm), and the p-nitrobenzyl (pNB) as protecting groups for cysteine and selenocysteine (Sec) during the tert-butyloxycarbonyl (Boc)-chemistry solid-phase peptide synthesis of oxytocin (OT). Two novel Sec building blocks (Nalpha-tert-butyloxycarbonyl-Se(acetamidomethyl)-L-selenocysteine (Boc-L-Sec(Acm)-OH) and Nalpha-tert-butyloxycarbonyl-S(4-nitrobenzyl)-L-selenocysteine (Boc-L-Sec(pNB)-OH)) were developed for this study. Six partially protected thio- and seleno-OT analogues were synthesized, purified, and exposed to neat trifluoroacetic acid (TFA) at temperatures of 25, 40, 50, and 60 degrees C for 1 h, and HF treatment at 0 degrees C for 1 h. Significant losses were observed for the Acm and Tacm group in TFA at temperatures greater than 25 degrees C and during HF treatment at 0 degrees C, whereas the pNB group remained intact. Removal of the pNB was achieved via reduction to the p-aminobenzyl group either with zinc in acetic acid in solution or via tin chloride in hydrochloric acid on solid support, followed by oxidative cleavage with iodine yielding the corresponding disulfide or diselenide bond. No major side reactions were observed. This study confirms the occasionally described Acm instability and underpins the development of the pNB group as an alternative for cysteine and Sec protection.
Design and Characterization of Superpotent Bivalent Ligands Targeting Oxytocin Receptor Dimers via a Channel-Like Structure
Publisher: American Chemical Society (ACS)
Date: 28-07-2016
DOI: 10.1021/ACS.JMEDCHEM.6B00564
Abstract: Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface. Moreover, in this arrangement, only the analogues with a well-defined spacer length (∼25 Å) precisely fit inside a channel-like passage between the two protomers of the dimer. The newly discovered oxytocin bivalent ligands represent a powerful tool for targeting dimeric OTR in neurodevelopmental and psychiatric disorders and, in general, provide a framework to untangle specific arrangements of G-protein coupled receptor dimers.
Mucosal Biofilms Are an Endoscopic Feature of Irritable Bowel Syndrome and Ulcerative Colitis
Publisher: Elsevier BV
Date: 10-2021
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