ORCID Profile
0000-0002-5794-266X
Current Organisation
Griffith University Institute for Glycomics
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Inorganic materials (incl. nanomaterials) | Proteins and Peptides | Biochemistry and cell biology | Biochemistry and Cell Biology | Structural biology (incl. macromolecular modelling) | Analytical Biochemistry |
Crop Protection Chemicals | Expanding Knowledge in the Biological Sciences | Infectious Diseases
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2022
DOI: 10.1101/2022.07.24.501068
Abstract: Human metapneumovirus (HMPV) is recognised as an important cause of pneumonia in infants, elderly, and immunocompromised in iduals worldwide. The absence of an antiviral treatment or vaccine strategy against HMPV infection creates a high burden on the global health care system. Drug repurposing has become increasingly attractive for the treatment of emerging and endemic diseases as it requires less research and development costs than traditional drug discovery. In this study, we developed an in vitro medium-throughput screening assay that allows for the identification of novel anti-HMPV drugs candidates. Out of ∼2400 compounds, we identified eleven candidates with a dose-dependent inhibitory activity against HMPV infection. Additionally, we further described the mode of action of five anti-HMPV candidates with low in vitro cytotoxicity. Two entry inhibitors, Evans Blue and aurintricarboxylic acid, and three post-entry inhibitors, mycophenolic acid, mycophenolate mofetil, and 2,3,4-trihydroxybenzaldehyde, were identified. Among them, the mycophenolic acid series displayed the highest levels of inhibition, due to the blockade of intracellular guanosine synthesis. Importantly, MPA has significant potential for drug repurposing as inhibitory levels are achieved below the approved human oral dose. Our drug-repurposing strategy proved to be useful for the rapid discovery of novel hit candidates to treat HMPV infection and provide promising novel templates for drug design. There is currently no treatment against acute HMPV infection. We developed a medium-throughput screening for drug repurposing against HMPV infection. Evaluation of a large drug library identified 5 candidates with low μM to nM IC 50 values against HMPV growth. The approved drug mycophenolic acid (MPA) is a nM inhibitor of HMPV in vitro infection Human MPA plasma levels upon oral dosing are 10x higher than MPA IC 50 against HMPV in vitro infection.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.ANTIVIRAL.2019.04.001
Abstract: Human parainfluenza viruses cause acute respiratory tract infections and disease predominantly in young children and immunocompromised in iduals. Currently, there are no vaccines to prevent hPIV infections, nor licensed anti-hPIV drugs. There is therefore a need for specific antiviral therapies to decrease the morbidity and mortality associated with hPIV diseases. Haemagglutinin-neuraminidase (HN) is one of two hPIV surface proteins with critical roles in host receptor recognition, binding and cleavage it has been explored as a key drug development target for the past few decades with variable success. Recent advancements in computational modelling and the availability of the X-ray crystal structure of hPIV3 HN have improved our understanding of the structural and mechanistic features of HN. This review explores structural features of the HN protein that are being exploited for structure-guided inhibitor design. We describe past and present hPIV HN inhibition strategies based on sialic acid scaffolds, together with other novel approaches that decrease hPIV infectivity. Although many HN inhibitors have been developed and evaluated as anti-hPIV agents, currently only a host-directed therapy (DAS181) has succeeded in phase II clinical drug trials. Hence, the review concludes with future considerations for targeting the specific function(s) of hPIV HN and suggestions for antiviral drug design.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.ANTIVIRAL.2022.105405
Abstract: Human metapneumoviruses have emerged in the past decades as an important global pathogen that causes severe upper and lower respiratory tract infections. Children under the age of 2, the elderly and immunocompromised in iduals are more susceptible to HMPV infection than the general population due to their suboptimal immune system. Despite the recent discovery of HMPV as a novel important respiratory virus, reports have rapidly described its epidemiology, biology, and pathogenesis. However, progress is still to be made in the development of vaccines and drugs against HMPV infection as none are currently available. Herein, we discuss the importance of HMPV and review the reported strategies for anti-HMPV drug candidates. We also present the fusion protein as a promising antiviral drug target due to its multiple roles in the HMPV lifecycle. This key viral protein has previously been targeted by a range of inhibitors, which will be discussed as they represent opportunities for future drug design.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6MD00519E
Abstract: We explore the structural features at C-4 of unsaturated N -acetylneuraminic acid required to access the 216-cavity in human parainfluenza virus hemagglutinin-neuraminidase.
Publisher: Springer Science and Business Media LLC
Date: 20-10-2014
DOI: 10.1038/NCOMMS6268
Abstract: Human parainfluenza viruses (hPIVs) cause upper and lower respiratory tract disease in children that results in a significant number of hospitalizations and impacts health systems worldwide. To date, neither antiviral drugs nor vaccines are approved for clinical use against parainfluenza virus, which reinforces the urgent need for new therapeutic discovery strategies. Here we use a multidisciplinary approach to develop potent inhibitors that target a structural feature within the hPIV type 3 haemagglutinin-neuraminidase (hPIV-3 HN). These dual-acting designer inhibitors represent the most potent designer compounds and efficiently block both hPIV cell entry and virion progeny release. We also define the binding mode of these inhibitors in the presence of whole-inactivated hPIV and recombinantly expressed hPIV-3 HN by Saturation Transfer Difference NMR spectroscopy. Collectively, our study provides an antiviral preclinical candidate and a new direction towards the discovery of potential anti-parainfluenza drugs.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6MD00519E
Abstract: We explore the structural features at C-4 of unsaturated N -acetylneuraminic acid required to access the 216-cavity in human parainfluenza virus hemagglutinin-neuraminidase.
Publisher: Wiley
Date: 15-03-2018
Abstract: Influenza virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for the development of anti-influenza agents is the virus surface protein sialidase. In the current study, we have discovered a highly potent inhibitor of influenza virus sialidase, based on a novel sialosyl sulfonate template. The synthesised 3-guanidino sialosyl α-sulfonate, a sulfonozanamivir analogue, inhibits viral replication in vitro at the nanomolar level, comparable to that of the anti-influenza drug zanamivir. Using protein X-ray crystallography we show that the sialosyl α-sulfonate template binds within the sialidase active site in a
Publisher: American Chemical Society (ACS)
Date: 25-04-2018
DOI: 10.1021/ACSCHEMBIO.8B00150
Abstract: A novel approach to human parainfluenza virus 3 (hPIV-3) inhibitor design has been evaluated by targeting an unexplored pocket within the active site region of the hemagglutinin-neuraminidase (HN) of the virus that is normally occluded upon ligand engagement. To explore this opportunity, we developed a highly efficient route to introduce nitrogen-based functionalities at the naturally unsubstituted C-3 position on the neuraminidase inhibitor template N-acyl-2,3-dehydro-2-deoxy-neuraminic acid ( N-acyl-Neu2en), via a regioselective 2,3-bromoazidation. Introduction of triazole substituents at C-3 on this template provided compounds with low micromolar inhibition of hPIV-3 HN neuraminidase activity, with the most potent having 48-fold improved potency over the corresponding C-3 unsubstituted analogue. However, the C-3-triazole N-acyl-Neu2en derivatives were significantly less active against the hemagglutinin function of the virus, with high micromolar IC
Publisher: MDPI AG
Date: 05-05-2019
DOI: 10.3390/V11050417
Abstract: Human parainfluenza virus (hPIV) infections are a major cause of respiratory tract illnesses in children, with currently no available vaccine or drug treatment. The surface glycoprotein haemagglutinin-neuraminidase (HN) of hPIV has a central role in the viral life cycle, including neuraminic acid-recognising receptor binding activity (early stage) and receptor-destroying activity (late stage), which makes it an ideal target for antiviral drug disovery. In this study, we showed that targeting the catalytic mechanism of hPIV-1 HN by a 2α,3β-difluoro derivative of the known hPIV-1 inhibitor, BCX 2798, produced more potent inhibition of the neuraminidase function which is reflected by a stronger inhibition of viral replication. The difluorosialic acid-based inhibitor efficiently blocked the neuraminidase activity of HN for a prolonged period of time relative to its unsaturated neuraminic acid (Neu2en) analogue, BCX 2798 and produced a more efficient inhibition of the HN neuraminidase activity as well as in vitro viral replication. This prolonged inhibition of the hPIV-1 HN protein suggests covalent binding of the inhibitor to a key catalytic amino acid, making this compound a new lead for a novel class of more potent hPIV-1 mechanism-based inhibitors.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1CC01593A
Abstract: An interdisciplinary approach determines that TriplatinNC binds to cell–surface heparan sulfate to protect cells from virus infection.
Publisher: Wiley
Date: 10-02-2015
Abstract: Human parainfluenza virus type 3 (hPIV-3) is one of the leading causes for lower respiratory tract disease in children, with neither an approved antiviral drug nor vaccine available to date. Understanding the catalytic mechanism of human parainfluenza virus haemagglutinin-neuraminidase (HN) protein is key to the design of specific inhibitors against this virus. Herein, we used (1) H NMR spectroscopy, X-ray crystallography, and virological assays to study the catalytic mechanism of the HN enzyme activity and have identified the conserved Tyr530 as a key amino acid involved in catalysis. A novel 2,3-difluorosialic acid derivative showed prolonged enzyme inhibition and was found to react and form a covalent bond with Tyr530. Furthermore, the novel derivative exhibited enhanced potency in virus blockade assays relative to its Neu2en analogue. These outcomes open the door for a new generation of potent inhibitors against hPIV-3 HN.
Publisher: American Society for Microbiology
Date: 27-04-2021
Abstract: SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases.
Publisher: American Society for Microbiology
Date: 18-10-2022
DOI: 10.1128/AAC.01008-22
Abstract: Human metapneumovirus (HMPV) is recognized as an important cause of pneumonia in infants, in the elderly, and in immunocompromised in iduals worldwide. The absence of an antiviral treatment or vaccine strategy against HMPV infection creates a high burden on the global health care system.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2016
DOI: 10.1038/SREP24138
Abstract: Human parainfluenza type-3 virus (hPIV-3) is one of the principal aetiological agents of acute respiratory illness in infants worldwide and also shows high disease severity in the elderly and immunocompromised, but neither therapies nor vaccines are available to treat or prevent infection, respectively. Using a multidisciplinary approach we report herein that the approved drug suramin acts as a non-competitive in vitro inhibitor of the hPIV-3 haemagglutinin-neuraminidase (HN). Furthermore, the drug inhibits viral replication in mammalian epithelial cells with an IC 50 of 30 μM, when applied post-adsorption. Significantly, we show in cell-based drug-combination studies using virus infection blockade assays, that suramin acts synergistically with the anti-influenza virus drug zanamivir. Our data suggests that lower concentrations of both drugs can be used to yield high levels of inhibition. Finally, using NMR spectroscopy and in silico docking simulations we confirmed that suramin binds HN simultaneously with zanamivir. This binding event occurs most likely in the vicinity of the protein primary binding site, resulting in an enhancement of the inhibitory potential of the N -acetylneuraminic acid-based inhibitor. This study offers a potentially exciting avenue for the treatment of parainfluenza infection by a combinatorial repurposing approach of well-established approved drugs.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2017
DOI: 10.1038/S41598-017-04656-Y
Abstract: Human parainfluenza viruses represent a leading cause of lower respiratory tract disease in children, with currently no available approved drug or vaccine. The viral surface glycoprotein haemagglutinin-neuraminidase (HN) represents an ideal antiviral target. Herein, we describe the first structure-based study on the rearrangement of key active site amino acid residues by an induced opening of the 216-loop, through the accommodation of appropriately functionalised neuraminic acid-based inhibitors. We discovered that the rearrangement is influenced by the degree of loop opening and is controlled by the neuraminic acid’s C-4 substituent’s size (large or small). In this study, we found that these rearrangements induce a butterfly effect of paramount importance in HN inhibitor design and define criteria for the ideal substituent size in two different categories of HN inhibitors and provide novel structural insight into the druggable viral HN protein.
Publisher: MDPI AG
Date: 24-09-2021
DOI: 10.3390/MI12101151
Abstract: This paper reports the design, development, and testing of a novel, yet simple and low-cost portable device for the rapid detection of SARS-CoV-2. The device performs loop mediated isothermal lification (LAMP) and provides visually distinguishable images of the fluorescence emitted from the s les. The device utilises an aluminium block embedded with a cartridge heater for isothermal heating of the s le and a single-board computer and camera for fluorescence detection. The device demonstrates promising results within 20 min using clinically relevant starting concentrations of the synthetic template. Time-to-signal data for this device are considerably lower compared to standard quantitative Polymerase Chain Reaction(qPCR) machine (~10–20 min vs. min) for 1 × 102 starting template copy number. The device in its fully optimized and characterized state can potentially be used as simple to operate, rapid, sensitive, and inexpensive platform for population screening as well as point-of-need severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) detection and patient management.
Start Date: 2019
End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 04-2022
End Date: 12-2023
Amount: $727,596.00
Funder: Australian Research Council
View Funded ActivityStart Date: 05-2023
End Date: 04-2024
Amount: $1,129,423.00
Funder: Australian Research Council
View Funded Activity