ORCID Profile
0000-0002-6089-5067
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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 | Characterisation of Biological Macromolecules | Medicinal and Biomolecular Chemistry | Biologically Active Molecules
ANZSRC Socio-Economic Objective (SEO)
Control of Animal Pests, Diseases and Exotic Species in Farmland, Arable Cropland and Permanent Cropland Environments | Expanding Knowledge in the Agricultural and Veterinary Sciences | Expanding Knowledge in the Biological Sciences |
Related Links
Publications
Cyclic peptides can engage a single binding pocket through highly divergent modes
Publisher: Proceedings of the National Academy of Sciences
Date: 12-10-2020
Abstract: Large DNA-encoded libraries of cyclic peptides are emerging as powerful sources of molecules to tackle challenging drug targets. The structural and functional ersity contained within these libraries is, however, little explored. Here we demonstrate that one such library contains members that use unexpectedly erse mechanisms to recognize the same surface on the same target proteins with high affinity and specificity. This range of binding modes is much larger than observed in natural ligands of the same proteins, demonstrating the power and versatility of the technology. Our data also reveal opportunities for the development of more sophisticated approaches to achieving specificity when trying to selectively target one member of a family of closely related proteins.
De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-12-2021
Abstract: Novel macrocyclic peptides are found that bind and modulate the function of the retromer membrane trafficking complex.
Sequence determinants of innate immune activation by short interfering RNAs
Publisher: Springer Science and Business Media LLC
Date: 2009
Discovery of Cyclic Peptide Ligands to the SARS-CoV-2 Spike Protein using mRNA Display
Publisher: Cold Spring Harbor Laboratory
Date: 23-12-2020
DOI: 10.1101/2020.12.22.424069
Abstract: The COVID-19 pandemic, caused by SARS-CoV-2, has led to substantial morbidity, mortality and disruption globally. Cellular entry of SARS-CoV-2 is mediated by the viral spike protein and affinity ligands to this surface protein have the potential for applications as antivirals and diagnostic reagents. Here, we describe the affinity selection of cyclic peptide ligands to the SARS-CoV-2 spike protein receptor binding domain (RBD) from three distinct libraries (in excess of a trillion molecules each) by mRNA display. We identified six high affinity molecules with dissociation constants ( K D ) in the nanomolar range (15-550 nM) to the RBD. The highest affinity ligand could be used as an affinity reagent to detect spike protein in solution by ELISA, and the co-crystal structure of this molecule bound to the RBD demonstrated that it binds to a cryptic binding site, displacing a β-strand near the C-terminus. Our findings provide key mechanistic insight into the binding of peptide ligands to the SARS-CoV-2 spike RBD and the ligands discovered in this work may find future use as reagents for diagnostic applications.
Discovery of Antiviral Cyclic Peptides Targeting the Main Protease of SARS-CoV-2 via mRNA Display
Publisher: Cold Spring Harbor Laboratory
Date: 24-08-2021
DOI: 10.1101/2021.08.23.457419
Abstract: Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (M pro ) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 M pro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of M pro complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S 1 and S 2 , respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these M pro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC 50 values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2.
Dz13, a DNAzyme targeting c-jun, induces off-target cytotoxicity in endothelial cells with features of nonapoptotic programmed cell death
Publisher: Mary Ann Liebert Inc
Date: 09-2008
Abstract: We have previously shown that Dz13, a catalytic DNA molecule (DNAzyme) designed against c-jun, is cytotoxic to nonquiescent cells by a mechanism independent of c-jun mRNA cleavage. In this report, we evaluated programmed cell death (PCD) pathways in order to gain further insight into the mechanism of action of Dz13. Using human dermal microvascular endothelial cells (HMEC-1), we found that Dz13-mediated cell death is characterized by mitochondrial depolarization, caspase-8 activation, lysosomal increase, and autophagosome formation. Classical DNA laddering and translocation of mitochondrial proteins were not observed. An array of inhibitors, including those targeting caspases, failed to abrogate cytotoxicity and mitochondrial depolarization. Cytotoxicity did not proceed from endoplasmic reticulum (ER) stress. The possible involvement of PARP-1 in Dz13-mediated cytotoxicity was indicated by its differential release as gauged by protein extraction data and its apparent binding to Dz13, as evidenced by protein pull-down experiments. This study on Dz13-mediated cytotoxicity presents a detailed investigation into the interplay of cell death effectors involved in apoptosis, autophagy, and necrosis, and demonstrates a novel form of oligonucleotide-mediated cytotoxicity with features of PCD.
Cytotoxic G-rich oligodeoxynucleotides: Putative protein targets and required sequence motif
Publisher: Oxford University Press (OUP)
Date: 22-06-2007
DOI: 10.1093/NAR/GKM465
Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming
Publisher: American Chemical Society (ACS)
Date: 28-05-2021
Discovery of Potent Cyclic Sulfopeptide Chemokine Inhibitors via Reprogrammed Genetic Code mRNA Display
Publisher: American Chemical Society (ACS)
Date: 24-04-2020
DOI: 10.1021/JACS.0C03152
De novomacrocyclic peptides for inhibiting, stabilising and probing the function of the Retromer endosomal trafficking complex
Publisher: Cold Spring Harbor Laboratory
Date: 04-12-2020
DOI: 10.1101/2020.12.03.410779
Abstract: The Retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signalling. Mutations in Retromer cause late-onset Parkinson’s disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its function we have created a novel series of macrocyclic peptides that bind Retromer with high affinity and specificity. Crystal structures show the majority of cyclic peptides bind to Vps29 via a Pro-Leu-containing sequence, structurally mimicking known interactors such as TBC1D5, and blocking their interaction with Retromer in vitro and in cells. By contrast, macrocyclic peptide RT-L4 binds Retromer at the Vps35-Vps26 interface and is a more effective molecular chaperone than reported small molecules, suggesting a new therapeutic avenue for targeting Retromer. Finally, tagged peptides can be used to probe the cellular localisation of Retromer and its functional interactions in cells, providing novel tools for studying Retromer function.
Possible protective effect of prenatal omega-3 long-chain polyunsaturated fatty acids supplementation on persistent wheeze and asthma in early childhood.
Publisher: BMJ
Date: 12-05-2017
Mutant N-ras preferentially drives human CD34+ hematopoietic progenitor cells into myeloid differentiation and proliferation both in vitro and in the NOD/SCID mouse
Publisher: Elsevier BV
Date: 09-2004
Discovery of Cyclic Peptide Ligands to the SARS-CoV-2 Spike Protein Using mRNA Display
Publisher: American Chemical Society (ACS)
Date: 27-05-2021
Primary leukocyte screens for innate immune agonists
Publisher: Elsevier BV
Date: 06-2009
Abstract: The innate immune system of mammals is a key defense mechanism against invading foreign pathogens. Innate immune stimulants may have applications as vaccine adjuvants as well as in the treatment of cancer and some viral diseases, and clinical studies have been performed using agonists of Toll-like receptors (TLRs) 7, 8, and 9. The high-throughput screens for such agonists have typically relied on the overexpression of a single TLR gene in an immortalized cell line and are inherently artificial systems that are restricted to the identification of agonists for a single receptor. The authors describe 2 assays for the identification of immunostimulants that employ primary human leukocytes cocultured with hepatitis C virus (HCV) replicon-expressing cells. In these assays, stimulation of innate immune pathways in leukocytes induces interferon (IFN) expression, which acts to inhibit HCV replication, providing a high-throughput and low-cost readout for leukocyte activation. These assays are highly sensitive and provide a physiologically relevant system for the identification of a broad range of immunostimulant agents.
Interfering ribonucleic acids that suppress expression of multiple unrelated genes
Publisher: Springer Science and Business Media LLC
Date: 2009
Antiviral cyclic peptides targeting the main protease of SARS-CoV-2
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D1SC06750H
Abstract: RaPID mRNA display was used for the discovery of antiviral cyclic peptides that potently and selectively inhibit SARS-CoV-2 M pro . The most potent inhibitor exhibited a novel binding mode, interacting with residues across the homodimer interface.
The role of IRF1 and IRF2 transcription factors in leukaemogenesis
Publisher: Bentham Science Publishers Ltd.
Date: 10-2006
DOI: 10.2174/156652306778520683
Abstract: Acute myeloid leukaemia (AML) is the most common form of leukaemia in adults. Although of the order of 75-85% of patients will achieve complete remission after induction chemotherapy, long-term survival is still relatively low. Despite the progress in the rational design of drugs in disorders such as chronic myeloid leukaemia, AML lacks a single specific pathogenomic event to act as a drug target. Interferon regulatory factor 1 (IRF1) is a member of a family of related proteins that act as transcriptional activators or repressors. IRF1 and its functional antagonist IRF2 originally discovered as transcription factors regulating the interferon-beta (IFN-beta) gene, are involved in the regulation of normal haematopoiesis and leukaemogenesis. IRF1 appears to act as a tumour suppressor gene and IRF2 as an oncogene. IRF1 acts to repress IRF2 function through the repression of cyclin-dependent kinase (CDK) inhibitor p21WAF1 critical for cell growth control. It appears that the tumour suppression function of IRF1 is abolished by IRF2. This review focuses on the interaction between IRF1 and IRF2 in myeloid development and leukaemogenesis, particularly in relation to the Ras signalling pathway. IRF2 may be a viable and specific therapeutic target in human leukaemia.
A sensitive dual-fluorescence reporter system enables positive selection of ras suppressors by suppression of ras-induced apoptosis
Publisher: Springer Science and Business Media LLC
Date: 22-09-2003
An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human β-Factor XIIa in a Cyclotide Scaffold
Publisher: American Chemical Society (ACS)
Date: 11-2021
DOI: 10.1021/JACS.1C07574
Abstract: Cyclotides are plant-derived peptides with complex structures shaped by their head-to-tail cyclic backbone and cystine knot core. These structural features underpin the native bioactivities of cyclotides, as well as their beneficial properties as pharmaceutical leads, including high proteolytic stability and cell permeability. However, their inherent structural complexity presents a challenge for cyclotide engineering, particularly for accessing libraries of sufficient chemical ersity to design potent and selective cyclotide variants. Here, we report a strategy using mRNA display enabling us to select potent cyclotide-based FXIIa inhibitors from a library comprising more than 10
Related Organisations
No related organisations have been discovered for Toby Passioura.
Related Funding Activities
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE220100060
Start Date: 06-2022
End Date: 06-2023
Amount: $772,676.00
Funder: Australian Research Council
View Funded Activity