ORCID Profile
0000-0001-5946-473X
Current Organisation
University of Adelaide
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Organic chemical synthesis | Medicinal and biomolecular chemistry | Proteins and peptides |
Publisher: Wiley
Date: 09-06-2022
Publisher: Wiley
Date: 20-05-2022
Abstract: A Ru(bpy) 3 Cl 2 photocatalyst is applied to the rapid trans to cis isomerization of a range of alkene‐containing pharmacological agents, including combretastatin A‐4 (CA‐4), a clinical candidate in oncology, and resveratrol derivatives, switching their configuration from inactive substances to potent cytotoxic agents. Selective in cellulo activation of the CA‐4 analog Res‐3M is demonstrated, along with its potent cytotoxicity and inhibition of microtubule dynamics.
Publisher: Wiley
Date: 04-02-2021
Publisher: John Wiley & Sons, Ltd
Date: 10-04-2017
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7CC00823F
Abstract: A robust, high yielding and epimerisation-free solid-phase method for accessing peptide selenoesters is reported.
Publisher: MDPI AG
Date: 20-10-2022
DOI: 10.3390/BIOM12101523
Abstract: Nucleic acids and proteins form two of the key classes of functional biomolecules. Through the ability to access specific protein-oligonucleotide conjugates, a broader range of functional molecules becomes accessible which leverages both the programmability and recognition potential of nucleic acids and the structural, chemical and functional ersity of proteins. Herein, we summarize the available conjugation strategies to access such chimeric molecules and highlight some key case study ex les within the field to showcase the power and utility of such technology.
Publisher: Wiley
Date: 09-03-2022
Abstract: Herein, we describe the development and application of a novel expressed protein selenoester ligation (EPSL) methodology for the one‐pot semi‐synthesis of modified proteins. EPSL harnesses the rapid kinetics of ligation reactions between modified synthetic selenopeptides and protein aryl selenoesters (generated from expressed intein fusion precursors) followed by in situ chemoselective deselenization to afford target proteins at concentrations that preclude the use of traditional ligation methods. The utility of the EPSL technology is showcased through the efficient semi‐synthesis of ubiquitinated polypeptides, lipidated analogues of the membrane‐associated GTPase YPT6, and site‐specifically phosphorylated variants of the oligomeric chaperone protein Hsp27 at high dilution.
Publisher: Wiley
Date: 05-11-2021
Abstract: Biomedical research has been empowered by tools that enable spatial and temporal control of biological systems. These have predominantly come from photocaged bioactive molecules (optochemical control N. Ankenbruck, T. Courtney, Y. Naro, A. Deiters, Angew. Chem. Int. Ed . 2018 , 57 , 2768–2798) and light‐dependent proteins (optogenetic control L. Fenno, O. Yizhar, K. Deisseroth, Annu. Rev. Neurosci . 2011 , 34 , 389–412). Recent advances in photocatalysis offer the opportunity to lify these strategies by providing new dimension of biorthogonality. Photocatalysis also empowers bioconjugation with unprecedented reactivities enabling new crosslinking chemistry or biomolecule functionalization, while merging photocatalysis with biocatalysis extends the scope of both of these powerful classes of transformation.
Publisher: Wiley
Date: 20-05-2022
Abstract: A Ru(bpy) 3 Cl 2 photocatalyst is applied to the rapid trans to cis isomerization of a range of alkene‐containing pharmacological agents, including combretastatin A‐4 (CA‐4), a clinical candidate in oncology, and resveratrol derivatives, switching their configuration from inactive substances to potent cytotoxic agents. Selective in cellulo activation of the CA‐4 analog Res‐3M is demonstrated, along with its potent cytotoxicity and inhibition of microtubule dynamics.
Publisher: Wiley
Date: 09-03-2022
Abstract: Herein, we describe the development and application of a novel expressed protein selenoester ligation (EPSL) methodology for the one-pot semi-synthesis of modified proteins. EPSL harnesses the rapid kinetics of ligation reactions between modified synthetic selenopeptides and protein aryl selenoesters (generated from expressed intein fusion precursors) followed by in situ chemoselective deselenization to afford target proteins at concentrations that preclude the use of traditional ligation methods. The utility of the EPSL technology is showcased through the efficient semi-synthesis of ubiquitinated polypeptides, lipidated analogues of the membrane-associated GTPase YPT6, and site-specifically phosphorylated variants of the oligomeric chaperone protein Hsp27 at high dilution.
Publisher: Wiley
Date: 09-06-2022
Publisher: Wiley
Date: 24-10-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4MD00406J
Abstract: The synthesis of a compound library based on a high throughput screening hit led to the discovery of several potent anti-trypanosomal agents.
Publisher: Springer Science and Business Media LLC
Date: 03-2017
DOI: 10.1038/NCOMMS14414
Abstract: Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis , the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.CBPA.2021.102104
Abstract: Nature is predicated on the ability to process large number of parallel signals to produce specific downstream outputs. Biosupramolecular networks are beginning to allow such processing power in synthetic systems, particularly through harnessing the recognition power of biomolecules. Such systems can be summarised through the reductionist view of containing inputs, circuitry motifs and functional outputs, with each of these elements able to be readily combined in a modular approach. Through the inherent 'plug and play' nature of these systems the field continues to rapidly expand, providing a wealth of new smart diagnostic and therapeutic systems.
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: 28-01-2021
Abstract: Blood feeding arthropods, such as leeches, ticks, flies and mosquitoes, provide a privileged source of peptidic anticoagulant molecules. These primarily operate through inhibition of the central coagulation protease thrombin by binding to the active site and either exosite I or exosite II. Herein, we describe the rational design of a novel class of trivalent thrombin inhibitors that simultaneously block both exosites as well as the active site. These engineered hybrids were synthesized using tandem diselenide‐selenoester ligation (DSL) and native chemical ligation (NCL) reactions in one‐pot. The most potent trivalent inhibitors possessed femtomolar inhibition constants against α‐thrombin and were selective over related coagulation proteases. A lead hybrid inhibitor possessed potent anticoagulant activity, blockade of both thrombin generation and platelet aggregation in vitro and efficacy in a murine thrombosis model at 1 mg kg −1 . The rational engineering approach described here lays the foundation for the development of potent and selective inhibitors for a range of other enzymatic targets that possess multiple sites for the disruption of protein–protein interactions, in addition to an active site.
Publisher: Wiley
Date: 04-02-2021
Publisher: Proceedings of the National Academy of Sciences
Date: 20-06-2019
Abstract: Cardiovascular disease represents a significant health challenge, with towering economic and social costs resulting from the high levels of associated morbidity and mortality. For conditions resulting from undesired blood clotting, treatment options remain limited and are accompanied by significant side effects. Using a rapid chemical ligation platform, 34 homogeneously modified variants of tick anticoagulant proteins were generated. Access to this synthetic protein library enabled key structure–activity relationships to be elucidated and revealed unexpected differences in the mechanism of thrombin inhibition by this group of otherwise closely related molecules. The synthetic platform reported here provides a unique means to expedite the generation and identification of polypeptide and protein therapeutic leads for clotting-associated diseases.
Publisher: Wiley
Date: 28-01-2021
Abstract: Blood feeding arthropods, such as leeches, ticks, flies and mosquitoes, provide a privileged source of peptidic anticoagulant molecules. These primarily operate through inhibition of the central coagulation protease thrombin by binding to the active site and either exosite I or exosite II. Herein, we describe the rational design of a novel class of trivalent thrombin inhibitors that simultaneously block both exosites as well as the active site. These engineered hybrids were synthesized using tandem diselenide‐selenoester ligation (DSL) and native chemical ligation (NCL) reactions in one‐pot. The most potent trivalent inhibitors possessed femtomolar inhibition constants against α‐thrombin and were selective over related coagulation proteases. A lead hybrid inhibitor possessed potent anticoagulant activity, blockade of both thrombin generation and platelet aggregation in vitro and efficacy in a murine thrombosis model at 1 mg kg −1 . The rational engineering approach described here lays the foundation for the development of potent and selective inhibitors for a range of other enzymatic targets that possess multiple sites for the disruption of protein–protein interactions, in addition to an active site.
Start Date: 01-2023
End Date: 01-2026
Amount: $537,000.00
Funder: Australian Research Council
View Funded Activity