ORCID Profile
0000-0002-5482-6225
Current Organisation
TU Wien
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Proteins and Peptides | Medicinal and Biomolecular Chemistry | Biologically Active Molecules | Characterisation of Biological Macromolecules
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Chemical Sciences | Control of Animal Pests, Diseases and Exotic Species in Farmland, Arable Cropland and Permanent Cropland Environments | Expanding Knowledge in the Agricultural and Veterinary Sciences |
Publisher: Springer Science and Business Media LLC
Date: 06-10-2020
Publisher: Wiley
Date: 30-07-2014
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1CB00045D
Abstract: Selective isotope labeling facilitates the analysis of effects of posttranslational modifications on protein structure and function.
Publisher: Wiley
Date: 2012
DOI: 10.1002/BIP.22121
Abstract: Cyclic disulfide-rich peptides ranging in size from ∼14 to 29 amino acids have been found in a wide variety of organisms and have exciting biological and medicinal applications due to their stability and structure. Many of these peptides can be chemically synthesized, but their small size and limited number of chromophore-containing amino acids make them difficult to quantify by methods routinely used for large proteins. A comparison of the precision and accuracy of gravimetric, UV- and NMR-based methods in current use for the quantification of small peptides is presented for a representative set of cyclic disulfide-rich peptides. The study shows that gravimetric and UV absorbance methods should be used with caution for small peptides and all methods should be carefully validated. For the routine quantification of small disulfide-rich peptides, we recommend comparison of the analytical reverse-phase high-performance liquid chromatography trace or UV absorbance at 214 nm with that of a standard peptide solution quantified by amino acid analysis. An accurate quantification method that is simple and cost effective will assist in comparison of inhibition and activity data between different laboratories and peptides and correct calculation of synthesis yields.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.BMC.2013.04.076
Abstract: DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand-receptor interactions.
Publisher: American Chemical Society (ACS)
Date: 15-09-2020
DOI: 10.26434/CHEMRXIV.12950942.V1
Abstract: Interactions between histones, which package DNA in eukaryotes, and nuclear proteins such as the high mobility group nucleosome-binding protein HMGN1 are important for regulating access to DNA. HMGN1 is a highly charged and intrinsically disordered protein (IDP) that is modified at several sites by posttranslational modifications (PTMs) - acetylation, phosphorylation and ADP-ribosylation. These PTMs are thought to affect cellular localisation of HMGN1 and its ability to bind nucleosomes however, little is known about how these PTMs regulate the structure and function of HMGN1 at a molecular level. Here, we combine the chemical biology tools of protein semi-synthesis and site-specific modification to generate a series of unique HMGN1 variants bearing precise PTMs at their N- and C-termini with segmental isotope labelling for NMR spectroscopy. This study demonstrates the power of combining protein semi-synthesis for introduction of site-specific PTMs with segmental isotope labelling for structural biology, allowing us to understand the roles of PTMs with atomic precision, from both structural and functional perspectives.
Publisher: Springer Science and Business Media LLC
Date: 04-2017
DOI: 10.1038/NATURE22033
Abstract: The crown-of-thorns starfish (COTS, the Acanthaster planci species group) is a highly fecund predator of reef-building corals throughout the Indo-Pacific region. COTS population outbreaks cause substantial loss of coral cover, diminishing the integrity and resilience of reef ecosystems. Here we sequenced genomes of COTS from the Great Barrier Reef, Australia and Okinawa, Japan to identify gene products that underlie species-specific communication and could potentially be used in biocontrol strategies. We focused on water-borne chemical plumes released from aggregating COTS, which make the normally sedentary starfish become highly active. Peptide sequences detected in these plumes by mass spectrometry are encoded in the COTS genome and expressed in external tissues. The exoproteome released by aggregating COTS consists largely of signalling factors and hydrolytic enzymes, and includes an expanded and rapidly evolving set of starfish-specific ependymin-related proteins. These secreted proteins may be detected by members of a large family of olfactory-receptor-like G-protein-coupled receptors that are expressed externally, sometimes in a sex-specific manner. This study provides insights into COTS-specific communication that may guide the generation of peptide mimetics for use on reefs with COTS outbreaks.
Publisher: Copernicus GmbH
Date: 24-02-2023
DOI: 10.5194/MR-4-57-2023
Abstract: Abstract. Peptides and proteins containing non-canonical amino acids (ncAAs) are a large and important class of biopolymers. They include non-ribosomally synthesised peptides, post-translationally modified proteins, expressed or synthesised proteins containing unnatural amino acids, and peptides and proteins that are chemically modified. Here, we describe a general procedure for generating atomic descriptions required to incorporate ncAAs within popular NMR structure determination software such as CYANA, CNS, Xplor-NIH and ARIA. This procedure is made publicly available via the existing Automated Topology Builder (ATB) server (atb.uq.edu.au, last access: 17 February 2023) with all submitted ncAAs stored in a dedicated database. The described procedure also includes a general method for linking of side chains of amino acids from CYANA templates. To ensure compatibility with other systems, atom names comply with IUPAC guidelines. In addition to describing the workflow, 3D models of complex natural products generated by CYANA are presented, including vancomycin. In order to demonstrate the manner in which the templates for ncAAs generated by the ATB can be used in practice, we use a combination of CYANA and CNS to solve the structure of a synthetic peptide designed to disrupt Alzheimer-related protein–protein interactions. Automating the generation of structural templates for ncAAs will extend the utility of NMR spectroscopy to studies of more complex biomolecules, with applications in the rapidly growing fields of synthetic biology and chemical biology. The procedures we outline can also be used to standardise the creation of structural templates for any amino acid and thus have the potential to impact structural biology more generally.
Publisher: Wiley
Date: 26-01-2018
Abstract: Multispecific and multivalent antibodies are seen as promising cancer therapeutics, and numerous antibody fragments and derivatives have been developed to exploit avidity effects that result in increased selectivity. Most of these multispecific and multivalent antibody strategies make use of recombinant expression of antigen-binding modules. In contrast, chemical synthesis and chemoselective ligations can be used to generate a variety of molecules with different numbers and combinations of binding moieties in a modular and homogeneous fashion. In this study we synthesized a series of targeted immune system engagers (ISErs) by using solid-phase peptide synthesis and chemoselective ligations. To explore avidity effects, we constructed molecules bearing different numbers and combinations of two "binder" peptides that target ephrin A2 and integrin α
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6OB00932H
Abstract: An adduct of dehydroascorbate with arginine forms during copper-catalysed azide–alkyne click reactions and resembles an advanced glycation end product.
Publisher: American Chemical Society (ACS)
Date: 15-09-2020
DOI: 10.26434/CHEMRXIV.12950942
Abstract: Interactions between histones, which package DNA in eukaryotes, and nuclear proteins such as the high mobility group nucleosome-binding protein HMGN1 are important for regulating access to DNA. HMGN1 is a highly charged and intrinsically disordered protein (IDP) that is modified at several sites by posttranslational modifications (PTMs) - acetylation, phosphorylation and ADP-ribosylation. These PTMs are thought to affect cellular localisation of HMGN1 and its ability to bind nucleosomes however, little is known about how these PTMs regulate the structure and function of HMGN1 at a molecular level. Here, we combine the chemical biology tools of protein semi-synthesis and site-specific modification to generate a series of unique HMGN1 variants bearing precise PTMs at their N- and C-termini with segmental isotope labelling for NMR spectroscopy. This study demonstrates the power of combining protein semi-synthesis for introduction of site-specific PTMs with segmental isotope labelling for structural biology, allowing us to understand the roles of PTMs with atomic precision, from both structural and functional perspectives. br
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.CHEMBIOL.2019.09.011
Abstract: The 8
Publisher: American Chemical Society (ACS)
Date: 26-04-2016
DOI: 10.1021/JACS.6B02575
Abstract: Enantiomeric forms of BTD-2, PG-1, and PM-1 were synthesized to delineate the structure and function of these β-sheet antimicrobial peptides. Activity and lipid-binding assays confirm that these peptides act via a receptor-independent mechanism involving membrane interaction. The racemic crystal structure of BTD-2 solved at 1.45 Å revealed a novel oligomeric form of β-sheet antimicrobial peptides within the unit cell: an antiparallel trimer, which we suggest might be related to its membrane-active form. The BTD-2 oligomer extends into a larger supramolecular state that spans the crystal lattice, featuring a steric-zipper motif that is common in structures of amyloid-forming peptides. The supramolecular structure of BTD-2 thus represents a new mode of fibril-like assembly not previously observed for antimicrobial peptides, providing structural evidence linking antimicrobial and amyloid peptides.
Publisher: Elsevier BV
Date: 10-2010
Publisher: Bentham Science Publishers Ltd.
Date: 26-03-2020
DOI: 10.2174/0929867325666171123204851
Abstract: Peptide-based pharmaceuticals have recently experienced a renaissance due to their ability to fill the gap between the two main classes of available drugs, small molecules and biologics. Peptides combine the high potency and selectivity typical of large proteins with some of the characteristic advantages of small molecules such as synthetic accessibility, stability and the potential of oral bioavailability. In the present manuscript we review the recent literature on selected peptide-based approaches for cancer treatment, emphasizing recent advances, advantages and challenges of each strategy. One of the applications in which peptide-based approaches have grown rapidly is cancer therapy, with a focus on new and established targets. We describe, with selected ex les, some of the novel peptide-based methods for cancer treatment that have been developed in the last few years, ranging from naturally-occurring and modified peptides to peptidedrug conjugates, peptide nanomaterials and peptide-based vaccines. This review brings out the emerging role of peptide-based strategies in oncology research, critically analyzing the advantages and limitations of these approaches and the potential for their development as effective anti-cancer therapies.
Publisher: American Chemical Society (ACS)
Date: 22-05-2019
DOI: 10.1021/ACS.BIOCHEM.9B00169
Abstract: Immune system engagers (ISErs) make up a new class of immunotherapeutics against cancer. They comprise two or more tumor-targeting peptides and an immune-stimulating effector peptide connected by inert polymer linkers. They are produced by solid phase peptide synthesis and share the specific targeting activities of antibodies (IgGs) but are much smaller in size and exploit a different immune-stimulating mechanism. Two ISErs (Y-9 and Y-59) that bind to the cancer cell markers integrin α3 and EphA2, respectively, are analyzed here with respect to their immune cell stimulation. We have previously shown that they activate formyl peptide receptors on myeloid immune cells and induce respiratory burst in neutrophils and myeloid chemotaxis in solution. It remained, however, unclear whether these molecules can stimulate immune cells while bound to tumor cells, an essential step in the hypothesized mode of action. Here, we demonstrate that ISEr Y-9 induced respiratory burst and caused a change in the shape of neutrophils when bound to the surface of protein A beads as a model of tumor cells. More importantly, tumor cell lines carrying receptor-bound Y-9 or Y-59 also activated neutrophils, evidenced by a significant change in shape. Interestingly, similar activation was induced by the supernatants of the cells incubated with ISEr, indicating that ISErs released from tumor cells, intact or degraded into fragments, significantly contributed to immune stimulation. These findings provide new evidence for the mode of action of ISErs, namely by targeting cancer cells and subsequently provoking an innate immune response against them.
Publisher: Wiley
Date: 16-02-2018
Publisher: Wiley
Date: 07-09-2011
Abstract: Cyclization of a peptide backbone is a relatively minor modification in one sense, in that it involves the addition of just one extra peptide bond to a protein sequence, but the consequences of this addition can be profound in terms of stability of the protein. Until recently, most studies of head‐to‐tail cyclic peptides were limited to rather small peptides, typically less than 12 amino acids in size, but over the last decade it has become clear that cyclization is readily applicable to a wide range of peptides and proteins, including those that contain one or more disulfide bonds. This article describes studies involving the solid phase peptide synthesis of two classes of disulfide‐rich peptides that contain a cystine knot and a cystine ladder motif, respectively. The cyclotides comprise around 30 amino acids, with their six conserved cysteine residues arranged in a cystine knot motif, whereas the θ‐defensins comprise 18 amino acids with the cysteine residues forming a cystine ladder.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2017
DOI: 10.1038/S41598-017-17627-0
Abstract: Immuno-oncology approaches mainly utilize monoclonal antibodies or protein-based scaffolds that bind with high affinity to cancer cells and can generate an immune response. Peptides can also bind with high affinity to cancer cells and are intermediate in size between antibodies and small molecules. They are also synthetically accessible and therefore easily modified to optimize their stability, binding affinity and selectivity. Here we describe the design of immune system engagers (ISErs), a novel class of synthetic peptide-based compounds that bind specifically to cancer cells and stimulate the immune system. A prototype, Y9, targets integrin α 3 , which is overexpressed on several cancer cells, and activates the immune system via a formyl methionine-containing effector peptide. Injection of Y9 leads to immune cell infiltration into tissue and prevents tumor formation in a guinea pig model. The anti-tumor activity and synthetic accessibility of Y9 illustrate that ISErs could be applied to a wide variety of targets and diseases.
Publisher: Wiley
Date: 2016
DOI: 10.1002/BIP.22767
Abstract: Peptides are attracting increasing interest from the pharmaceutical industry because of their specificity and ability to address novel targets, including protein-protein interactions. However, typically they require stabilization for therapeutic applications owing to their susceptibility to degradation by proteases. Advances in the ability to chemically synthesize peptides and the development of new side-chain and backbone ligation strategies provide new tools to stabilize bioactive peptide epitopes. Two such epitopes are LyP1, a nine residue peptide that localizes to tumor cells and has potential as an anticancer therapeutic, and RGDS, a tetrapeptide shown to bind to survivin and induce apoptosis. Here we applied a variety of strategies for the stabilization of LyP1 and RGDS, including side-chain cyclization using "click" chemistry and "grafting" the epitopes into two naturally occurring cyclic peptide scaffolds, i.e., θ-defensins and cyclotides. NMR data showed that the three-disulfide θ-defensin and cyclotide scaffolds accommodated the LyP1 and RGDS epitopes but that scaffolds with fewer disulfide bonds were structurally compromised by inclusion of the LyP1 epitope. LyP1, LyP1-, and RGDS-grafted peptides that were largely unstructured also had reduced resistance to degradation in human serum, showing that grafting into a stable cyclic scaffold is an effective strategy for increasing the stability of a bioactive peptide epitope. Overall, the study demonstrates several methods for stabilizing peptide epitopes using side-chain or backbone cyclization and illustrates their potential in peptide drug design.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0CB00175A
Abstract: Using protein semi-synthesis, segmentally isotope-labelled variants of nucleosome-binding protein HMGN1 were generated with site-specific posttranslational modifications to explore their structural and functional effects.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Wiley
Date: 30-07-2014
Publisher: Wiley
Date: 02-01-2014
Abstract: Peptides have the specificity and size required to target the protein-protein interactions involved in many diseases. Some cyclic peptides have been utilised as scaffolds for peptide drugs because of their stability however, other cyclic peptide scaffolds remain to be explored. θ-Defensins are cyclic peptides from mammals they are characterised by a cyclic cystine ladder motif and have low haemolytic and cytotoxic activity. Here we demonstrate the potential of the cyclic cystine ladder as a scaffold for peptide drug design by introducing the integrin-binding Arg-Gly-Asp (RGD) motif into the θ-defensin RTD-1. The most active analogue had an IC50 of 18 nM for the αv β3 integrin as well as high serum stability, thus demonstrating that a desired bioactivity can be imparted to the cyclic cystine ladder. This study highlights how θ-defensins can provide a stable and conformationally restrained scaffold for bioactive epitopes in a β-strand or turn conformation. Furthermore, the symmetry of the cyclic cystine ladder presents the opportunity to design peptides with dual bioactive epitopes to increase activity and specificity.
Publisher: American Chemical Society (ACS)
Date: 10-08-2017
Publisher: Wiley
Date: 06-11-2017
DOI: 10.1002/PSC.3051
Abstract: A prominent target of monoclonal antibodies as targeted therapies for cancer is the epidermal growth factor receptor, which is overexpressed on the surface of various cancer cell types. Its natural binder, the epidermal growth factor (EGF), is a 53 amino acid polypeptide. Anticancer synthetic targeted immune system engagers (ISErs) comprising two 'binder' peptides, which are attached to a scaffold conveying immune stimulating 'effector' properties, via monodisperse polyethylene glycol chains. So far, preparation of ISErs has been limited to the use of small peptides (8-20 amino acids) as binding functionalities, and they have been entirely synthesized by solid phase peptide synthesis. Here, we describe a synthetic and a semisynthetic approach for the preparation of an ISEr bearing two murine EGF molecules as binding entities (ISEr-EGF
Publisher: Wiley
Date: 21-06-2023
Abstract: The early‐career researchers showcased in this ChemBioTalents special collection, and many others who have established their independent scientific careers over the last three years, have experienced a unique set of circumstances. The Covid‐19 pandemic necessitated new forms of communication and interpersonal interactions: From online interviews and virtual networking to relocating and establishing labs during a pandemic, we faced many challenges, but also unexpected opportunities. In this perspective, we reflect on this unique and formative time through personal anecdotes and viewpoints, trying to capture erse experiences from the Chemical Biology community and beyond. We have tried to get a broad and varied set of perspectives, however, the selection is biased towards researchers who were able to start their independent careers. 1
Publisher: American Chemical Society (ACS)
Date: 19-05-2011
DOI: 10.1021/JO200520V
Abstract: Cyclotides are head-to-tail cyclic peptides that contain a cystine knot motif built from six conserved cysteine residues. They occur in plants of the Rubiaceae, Violaceae, Cucurbitaceae, and Fabaceae families and, aside from their natural role in host defense, have a range of interesting pharmaceutical activities, including anti-HIV activity. The variation seen in sequences of their six backbone loops has resulted in cyclotides being described as a natural combinatorial template. Their exceptional stability and resistance to enzymatic degradation has led to their use as scaffolds for peptide-based drug design. To underpin such applications, methods for the chemical synthesis of cyclotides have been developed and are described here. Cyclization using thioester chemistry has been instrumental in the synthesis of cyclotides for structure-activity studies. This approach involves a native chemical ligation reaction between an N-terminal Cys and a C-terminal thioester in the linear cyclotide precursor. Since cyclotides contain six Cys residues their syntheses can be designed around any of six linear precursors, thus providing flexibility in synthesis. The ease with which cyclotides fold, despite their topologically complex knot motif, as well as the ability to introduce combinatorial variation in the loops, makes cyclotides a promising drug-design scaffold.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1MD00182E
Abstract: Cone snail venoms are richly decorated with posttranslational modifications. We show that tyrosine sulfation and C-terminal amidation increase the structural stability and binding of α-conotoxins.
Publisher: Springer Science and Business Media LLC
Date: 17-07-2019
Publisher: Elsevier BV
Date: 03-2018
Publisher: Elsevier BV
Date: 04-2013
Publisher: American Chemical Society (ACS)
Date: 20-11-2012
DOI: 10.1021/BI301363A
Abstract: The θ-defensins are, to date, the only known ribosomally synthesized cyclic peptides in mammals, and they have promising antimicrobial bioactivities. The characteristic structural motif of the θ-defensins is the cyclic cystine ladder, comprising a cyclic peptide backbone and three parallel disulfide bonds. In contrast to the cyclic cystine knot, which characterizes the plant cyclotides, the cyclic cystine ladder has not been as well described as a structural motif. Here we report the solution structures and nuclear magnetic resonance relaxation properties in aqueous solution of three representative θ-defensins from different species. Our data suggest that the θ-defensins are more rigid and structurally defined than previously thought. In addition, all three θ-defensins were found to self-associate in aqueous solution in a concentration-dependent and reversible manner, a property that might have a role in their mechanism of action. The structural definition of the θ-defensins and the cyclic cystine ladder will help to guide exploitation of these molecules as structural frameworks for the design of peptide drugs.
Publisher: Wiley
Date: 09-08-2016
DOI: 10.1002/BIT.25993
Publisher: Frontiers Media SA
Date: 06-03-2019
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8CS00573G
Abstract: Combining modern synthetic and molecular biology toolkits, native chemical ligation and expressed protein ligation enables robust access to modified proteins.
Publisher: Wiley
Date: 26-11-2021
DOI: 10.1002/PEP2.24250
Abstract: Defensins are key components of both innate and adaptive immune responses to pathogens. Cryptdins are mouse alpha‐defensins that are secreted from Paneth cells in the small intestine and have disulfide‐stabilised structures and antibacterial activities against both Gram‐positive and Gram‐negative bacteria. The folding and three‐dimensional structures of alpha‐defensins are thought to depend on a conserved glycine residue that forms a β‐bulge. Here we investigated the role of this conserved glycine at position 19 of cryptdin‐4 (Crp4) in terms of the folding, structure and stability. A Crp4 variant with D‐Ala at position 19 folded efficiently, was stabilised by a large number of hydrogen bonds, and resisted proteolysis in simulated intestinal fluid. Although a variant with L‐Ala at position 19 was able to adopt the correct fold, it showed less efficient folding and was degraded more rapidly than the D‐Ala variant. These results demonstrate the key role that glycine residues can have in folding of bioactive peptides and can provide insights to guide design of stable antimicrobial peptides that fold efficiently.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.BMC.2010.11.062
Abstract: The diethyl esters and disodium salts of a range of heteroarylcarbamoylphosphonic acids have been prepared and evaluated as analogues of the highly active DOXP-reductoisomerase (DXR) inhibitor, fosmidomycin. Computer-simulated docking studies, Saturation Transfer Difference (STD) NMR analysis and enzyme inhibition assays have been used to explore enzyme-binding and -inhibition potential, while in silico analysis of the DXR active site has highlighted the importance of including a well-parameterised metal co-factor in docking studies and has revealed the availability of an additional binding pocket to guide future drug design.
Publisher: Copernicus GmbH
Date: 29-11-2022
DOI: 10.5194/MR-2022-22
Abstract: Abstract. Peptides and proteins containing non-canonical amino acids (ncAAs) are a large and important class of biopolymers. They include non-ribosomally synthesised peptides, post-translationally modified proteins, expressed or synthesised proteins containing unnatural amino acids, and peptides and proteins that are chemically modified. Here, we describe a general procedure for generating atomic descriptions required to incorporate ncAAs within popular NMR structure determination software such as CYANA, CNS, Xplor-NIH and ARIA. This procedure is made publicly available via the existing Automated Topology Builder (ATB) server (atb.uq.edu.au) with all submitted ncAAs stored in a dedicated database. The described procedure also includes a general method for linking of sidechains of amino acids from CYANA templates. To ensure compatibility with other systems, atom names comply with IUPAC guidelines. In addition to describing the workflow, 3D models of complex natural products generated by CYANA are presented, including vancomycin. In order to demonstrate the manner in which the templates for ncAAs generated by the ATB can be used in practice we use a combination of CYANA and CNS to solve the structure of a synthetic peptide designed to disrupt Alzheimer-related protein-protein interactions. Automating the generation of structural templates for ncAAs will extend the utility of NMR spectroscopy to studies of more complex biomolecules, with applications in the rapidly growing fields of synthetic and chemical biology. The procedures we outline can also be used to standardise the creation of structural templates for any amino acid and thus have the potential to impact structural biology more generally.
Publisher: Wiley
Date: 11-2015
DOI: 10.1002/BIP.22699
Abstract: Peptide backbone cyclization is a widely used approach to improve the activity and stability of small peptides but until recently it had not been applied to peptides with multiple disulfide bonds. Conotoxins are disulfide-rich conopeptides derived from the venoms of cone snails that have applications in drug design and development. However, because of their peptidic nature, they can suffer from poor bioavailability and poor stability in vivo. In this study two P-superfamily conotoxins, gm9a and bru9a, were backbone cyclized by joining the N- and C-termini with short peptide linkers using intramolecular native chemical ligation chemistry. The cyclized derivatives had conformations similar to the native peptides showing that backbone cyclization can be applied to three disulfide-bonded peptides with cystine knot motifs. Cyclic gm9a was more potent at high voltage-activated (HVA) calcium channels than its acyclic counterpart, highlighting the value of this approach in developing active and stable conotoxins containing cyclic cystine knot motifs.
Publisher: American Chemical Society (ACS)
Date: 25-11-2014
DOI: 10.1021/JP507754C
Start Date: 06-2022
End Date: 06-2023
Amount: $772,676.00
Funder: Australian Research Council
View Funded ActivityStart Date: 10-2022
End Date: 10-2025
Amount: $495,000.00
Funder: Australian Research Council
View Funded Activity