ORCID Profile
0000-0003-3445-2104
Current Organisation
University of Queensland
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
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)
Infectious Diseases | Medicinal and Biomolecular Chemistry | Cheminformatics and Quantitative Structure-Activity Relationships | Bioinformatics | Systems Biology | Biologically Active Molecules
ANZSRC Socio-Economic Objective (SEO)
Human Biological Preventatives (e.g. Vaccines) | Human Diagnostics | Human Pharmaceutical Treatments (e.g. Antibiotics) |
Related Links
Publications
(Z)-N'-(1H-Benzo[d]imidazol-2-Yl)-Arylimidamide Adducts of 2-Aminobenzimidazole and Aromatic Nitriles: Structural and Spectroscopic Proof of Regiochemical and Stereochemical Outcomes
Publisher: American Chemical Society (ACS)
Date: 28-02-2019
DOI: 10.26434/CHEMRXIV.7777085.V1
Abstract: The selection of a core scaffold or template is of enormous importance in medicinal chemistry. Benzimidazoles are a recurring fragment in medicinal chemistry, and the 2-amino derivative is a versatile ex le in lead generation. Alkylated and acylated ex les abound, however, alternative linkage chemistries leading do more erse structures are needed. Here we discuss the regiochemistry of nucleophilic addition of 2-aminobenzimidazole to nitriles, leading to imidamide (amidine) adducts. Additionally, we use extensive NMR analysis and ultimately X-ray crystallography to demonstrate both the regiochemistry and stereochemistry of the addition products, arising from derivatisation of the exocylic 2-amino group.
Why are there so few Australian chemists on Twitter?
Publisher: Figshare
Date: 2019
CCDC 1891428: Experimental Crystal Structure Determination
Publisher: Cambridge Crystallographic Data Centre
Date: 2019
1H NMR evidence for the formation of vinyllead triacetates. The reactions of vinylmercury, vinyltin, and vinylboronic acids with lead tetraacetate
Publisher: Elsevier BV
Date: 1996
(Z)-N'-(1H-Benzo[d]imidazol-2-Yl)-Arylimidamide Adducts of 2-Aminobenzimidazole and Aromatic Nitriles: Structural and Spectroscopic Proof of Regiochemical and Stereochemical Outcomes
Publisher: American Chemical Society (ACS)
Date: 28-02-2019
DOI: 10.26434/CHEMRXIV.7777085
Abstract: The selection of a core scaffold or template is of enormous importance in medicinal chemistry. Benzimidazoles are a recurring fragment in medicinal chemistry, and the 2-amino derivative is a versatile ex le in lead generation. Alkylated and acylated ex les abound, however, alternative linkage chemistries leading do more erse structures are needed. br Here we discuss the regiochemistry of nucleophilic addition of 2-aminobenzimidazole to nitriles, leading to imidamide (amidine) adducts. Additionally, we use extensive NMR analysis and ultimately X-ray crystallography to demonstrate both the regiochemistry and stereochemistry of the addition products, arising from derivatisation of the exocylic 2-amino group.
Downsizing Proteins Without Losing Potency or Function
Publisher: Prompt Scientific Publishing
Date: 2015
Vinyl cation formation by decomposition of vinyllead(IV) triacetates. Part 2
Publisher: Royal Society of Chemistry (RSC)
Date: 1991
DOI: 10.1039/P19910002455
Vinyl cation formation by decomposition of vinyl-lead triacetates. The reactions of vinylmercury and vinyltin compounds with lead tetra-acetate
Publisher: Royal Society of Chemistry (RSC)
Date: 1990
DOI: 10.1039/P19900002645
Ethyl 3-Acetoxy-3-methyl-5-phenylpentanoate
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M60
3-Hydroxy-3-methyl-5-phenylpentanoic Acid
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M61
Macrocyclic Peptides as Ligands for Cellular Receptors. When a little rigidity is just right.....
Publisher: Figshare
Date: 2019
Synthesis and cannabinoid activity of 1-substituted-indole-3-oxadiazole derivatives: Novel agonists for the CB1 receptor
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.EJMECH.2007.04.007
Abstract: An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB(1) agonists. It is hoped that compounds of this type will have clinical utility in pain control, and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of a series of 1-substituted-indole-3-oxadiazoles as potential CB(1) agonists.
Ethyl (E)-3-methyl-5-phenyl-2-pentenoate
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M51
Ethyl (Z)-3-Methyl-5-phenyl-2-pentenoate
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M52
(E)-3-Methyl-5-phenyl-2-pentenoic Acid
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M53
Insights to substrate binding and processing by West Nile Virus NS3 protease through combined modeling, protease mutagenesis, and kinetic studies
Publisher: Elsevier BV
Date: 12-2006
Electrophilic vinylations by vinyllead triacetates and tribenzoates generated by tin–lead exchange
Publisher: Royal Society of Chemistry (RSC)
Date: 1992
DOI: 10.1039/P19920001911
(Z)-3-Methyl-5-phenyl-2-pentenoic Acid
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M54
Potent inhibitors of West Nile Virus NS2B/NS3 protease
Publisher: Figshare
Date: 2019
Structural mimicry of two cytochrome b562 interhelical loops using macrocycles constrained by oxazoles and thiazoles
Publisher: American Chemical Society (ACS)
Date: 13-04-2005
DOI: 10.1021/JA0455300
Abstract: A major chemical challenge is the structural mimicry of discontinuous protein surfaces brought into close proximity through polypeptide folding. We report the design, synthesis, and solution structure of a highly functionalized saddle-shaped macrocyclic scaffold, constrained by oxazoles and thiazoles, supporting two short peptide loops projecting orthogonally from the same face of the scaffold. This structural mimetic of two interhelical loops of cytochrome b(562) illustrates a promising approach to structurally mimicking discontinuous loops of proteins.
2(S,R),3(R,S)-2,3-Dibromo-3-methyl-5-phenyl-2-pentanoic Acid
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M55
2(R,S),3(S,R)-2,3-Dibromo-3-methyl-5-phenyl-2-pentanoic Acid
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M56
(E)-1-Bromo-2-methyl-4-phenyl-1-butene
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M58
Ethyl 3-Hydroxy-3-methyl-5-phenylpentanoate
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M59
Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists
Publisher: Springer Science and Business Media LLC
Date: 20-04-2016
DOI: 10.1038/SREP24575
Abstract: Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action ( t 1/2 ~ 20 h) than W54011 or JJ47 ( t 1/2 ~ 1–3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.
Homology Models of Coronavirus 3CLpro Protease
Publisher: American Chemical Society (ACS)
Date: 04-02-2020
DOI: 10.26434/CHEMRXIV.11637294.V2
Abstract: A regional outbreak of pneumonia in Wuhan, Hubei Province of China in late 2019 was associated with a novel coronavirus. Rapid release of genomic data for the isolated virus enabled the construction of first-generation homology models of the new CoV 3CL pro cysteine protease. Whilst the overall viral genome was most closely associated with bat coronaviruses, the main protease is most closely related (96% identity) to SARS CoV protease.
Homology Models of Coronavirus 2019-nCoV 3CLpro Protease
Publisher: American Chemical Society (ACS)
Date: 05-02-2020
DOI: 10.26434/CHEMRXIV.11637294.V3
Abstract: A regional outbreak of pneumonia in Wuhan, Hubei Province of China in late 2019 was associated with a novel coronavirus. Rapid release of genomic data for the isolated virus enabled the construction of first-generation homology models of the new CoV 3CL pro cysteine protease. Whilst the overall viral genome was most closely associated with bat coronaviruses, the main protease is most closely related (96% identity) to SARS CoV protease.
Homology Models of Wuhan Coronavirus 3CLpro Protease
Publisher: American Chemical Society (ACS)
Date: 24-01-2020
DOI: 10.26434/CHEMRXIV.11637294.V1
Abstract: A regional outbreak of pneumonia in Wuhan, Hubei Province of China in late 2019 was associated with a novel coronavirus. Rapid release of genomic data for the isolated virus enabled the construction of first-generation homology models of the new CoV 3CL pro cysteine protease. Whilst the overall viral genome was most closely associated with bat coronaviruses, the main protease is most closely related (96% identity) to SARS CoV protease.
Base-sensitivity of arginine alpha-ketoamide inhibitors of serine proteases
Publisher: CSIRO Publishing
Date: 2009
DOI: 10.1071/CH09150
Abstract: Serine protease enzymes use a serine hydroxyl group to catalyze hydrolysis of polypeptides. They are important in immunity, blood clotting, digestion, and as therapeutic or diagnostic targets for cancer, diabetes, stroke, inflammatory diseases, and viral infections. Their inhibitors typically possess an electrophile that reacts with the nucleophilic hydroxyl group of the catalytic serine. The α-ketoamide is a valuable electrophile in inhibitor discovery as it permits synthetic elaboration to both sides, unlike other electrophiles. Here we show that an α-ketoamide is unstable above pH 7 when adjacent to the C-terminus of arginine – the guanidine side chain condenses with the α-ketoamide at the keto group rather than the amide carbonyl to form a six-membered hemiaminal rather than a seven-membered lactam.
Structure of West Nile Virus NS3 Protease: Ligand Stabilization of the Catalytic Conformation
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.JMB.2008.11.026
Abstract: Over the last decade, West Nile virus has spread rapidly via mosquito transmission from infected migratory birds to humans. One potential therapeutic approach to treating infection is to inhibit the virally encoded serine protease that is essential for viral replication. Here we report the crystal structure of the viral NS3 protease tethered to its essential NS2B cofactor and bound to a potent substrate-based tripeptide inhibitor, 2-naphthoyl-Lys-Lys-Arg-H (K(i)=41 nM), capped at the N-terminus by 2-naphthoyl and capped at the C-terminus by aldehyde. An important and unexpected feature of this structure is the presence of two conformations of the catalytic histidine suggesting a role for ligand stabilization of the catalytically competent His conformation. Analysis of other West Nile virus NS3 protease structures and related serine proteases supports this hypothesis, suggesting that the common catalytic mechanism involves an induced-fit mechanism.
Supplementary Data tables for: Orally absorbed cyclic peptides
Publisher: No publisher found
Date: 2019
Orally Absorbed Cyclic Peptides
Publisher: American Chemical Society (ACS)
Date: 25-05-2017
DOI: 10.1021/ACS.CHEMREV.6B00838
Abstract: Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol-water partitioning, hydrogen bond donors/acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption.
Simultaneous uncoupled expression and purification of the Dengue virus NS3 protease and NS2B co-factor domain
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.PEP.2015.11.022
Abstract: Dengue Virus (DENV) infection is responsible for the world's most significant insect-borne viral disease. Despite an increasing global impact, there are neither prophylactic nor therapeutic options available for the effective treatment of DENV infection. An attractive target for antiviral drugs is the virally encoded trypsin-like serine protease (NS3pro) and its associated cofactor (NS2B). The NS2B-NS3pro complex is responsible for cleaving the viral polyprotein into separate functional viral proteins, and is therefore essential for replication. Recombinant expression of an active NS2B-NS3 protease has primarily been based on constructs linking the C-terminus of the approximately 40 amino acid hydrophilic cofactor domain of NS2B to the N-terminus of NS3pro via a flexible glycine linker. The resulting complex can be expressed in high yield, is soluble and catalytically active and has been used for most in vitro screening, inhibitor, and X-ray crystallographic studies over the last 15 years. Despite extensive analysis, no inhibitor drug candidates have been identified yet. Moreover, the effect of the artificial linker introduced between the protease and its cofactor is unknown. Two alternate methods for bacterial expression of non-covalently linked, catalytically active, NS2B-NS3pro complex are described here along with a comparison of the kinetics of substrate proteolysis and binding affinities of substrate-based aldehyde inhibitors. Both expression methods produced high yields of soluble protein with improved substrate proteolysis kinetics and inhibitor binding compared to their glycine-linked equivalent. The non-covalent association between NS2B and NS3pro is predicted to be more relevant for examining inhibitors that target cofactor-protease interactions rather than the protease active site. Furthermore, these approaches offer alternative strategies for the high yield co-expression of other protein assemblies.
Potent inhibitors of West Nile Virus NS2B/NS3 protease
Publisher: Figshare
Date: 2019
West Nile Virus NS2B/NS3 protease as an antiviral target
Publisher: Bentham Science Publishers Ltd.
Date: 11-2008
DOI: 10.2174/092986708786242804
Abstract: West Nile Virus (WNV) has spread rapidly during the last decade across five continents causing disease and fatalities in humans and mammals. It highlights the serious threat to both our health and the economy posed by viruses crossing species, in this case from migratory birds via mosquitoes to mammals. There is no vaccine or antiviral drug for treating WNV infection. One attractive target for antiviral development is a viral trypsin-like serine protease, encoded by the N-terminal 184 amino acids of NS3, which is only active when tethered to its cofactor, NS2B. This protease, NS2B/NS3pro, cleaves the viral polyprotein to release structural and non-structural viral proteins that are essential in viral replication and assembly of new virus particles. Disruption of this protease activity is lethal for virus replication. The NS3 protein also has other enzymes within its sequence (helicase, nucleoside triphosphatase, RNA triphosphatase), all of which are tightly regulated through localisation within membranous compartments in the infected cell. This review describes the various roles of NS3, focussing on NS2B-NS3 protease and its function and regulation in WNV replication and infection. Current advances towards development of antiviral inhibitors of NS2B/NS3pro are examined along with obstacles to their development as an antiviral therapy.
Downsizing a human inflammatory protein to a small molecule with equal potency and functionality
Publisher: Springer Science and Business Media LLC
Date: 21-11-2013
DOI: 10.1038/NCOMMS3802
Abstract: A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turn-inducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weight <500 Da) examined for receptor affinity and cellular responses have the same high potencies, functional profile and specificity of action as C3a protein, but greater plasma stability and bioavailability.
Flavones are inhibitors of HIV-1 proteinase
Publisher: Elsevier BV
Date: 10-1992
DOI: 10.1016/0006-291X(92)91103-W
Abstract: Substituted gamma-chromones were found to weakly inhibit HIV-1 proteinase, an important enzyme in the replication and processing of the AIDS virus. Chromones bearing hydroxyl substituents and a phenolic group at the 2-position (flavones) were the most active compounds and structure-activity relationships for a limited series of flavone inhibitors are presented. Dixon plots are reported and a possible mechanism for flavone-induced inhibition is proposed. The results are also compared with those for some structurally related non-peptidic inhibitors of HIV-1 proteinase. Since some flavonoid compounds have already been shown to have antiviral activity against AIDS, the present observations of anti-HIV-1 proteinase activity may be particularly significant.
ChemInform Abstract: Lithium Perchlorate Accelerated Friedel—Crafts Addition of Furans to β‐Nitrostyrenes.
Publisher: Wiley
Date: 27-03-2014
Structure-activity relationships for macrocyclic peptidomimetic inhibitors of HIV-1 protease.
Publisher: Elsevier BV
Date: 11-1996
Site-directed mutagenesis and kinetic studies of the West Nile virus NS3 protease identify key enzyme-substrate interactions
Publisher: Elsevier BV
Date: 2005
bis-[(Z)-5-Phenyl-2-penten-2-yl]mercury
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M70
Ethyl (E)-3-(2-Methoxyphenyl)-2-butenoate
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M71
Lithium perchlorate accelerated Friedel–Crafts addition of furans to β-nitrostyrenes
Publisher: Elsevier BV
Date: 12-2013
Ethyl (Z)-3-(2-Methoxyphenyl)-2-butenoate
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M72
Homology Models of the Papain-Like Protease PLpro from Coronavirus 2019-nCoV
Publisher: American Chemical Society (ACS)
Date: 04-02-2020
DOI: 10.26434/CHEMRXIV.11799705.V1
Abstract: The December 2019 outbreak of pneumonia in Wuhan, Hubei Province of China was rapidly linked to a novel coronavirus 2019-nCoV. The rapid spread and severity of the virus has led the World Health Organization to declare it a Public Health Emergency of International Concern. We recently described the first homology models of the main 3CL protease from 2019-nCoV, and now present models of the other viral protease, the papain-like protease or PLpro. Whilst the overall viral genome is most closely associated with bat coronaviruses, no bat PLpro crystal structures are known. Wuhan 2019-nCoV PLpro is most closely related to a bat coronavirus PLpro (97% identity), then SARS (80 %) and MERS (29%) and the most promising models presented here are prepared from SARS crystal structure templates.
Ethyl (E)-2-Methyl-5-phenyl-2-pentenoate
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M62
Macrocyclic Peptides as Ligands for Cellular Receptors. When a little rigidity is just right.....
Publisher: Figshare
Date: 2019
Ethyl (Z)-2-Methyl-5-phenyl-2-pentenoate
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M63
(E)-2-Methyl-5-phenyl-2-pentenoic Acid
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M64
Three Homology Models of PAR2 Derived from Different Templates: Application to Antagonist Discovery
Publisher: American Chemical Society (ACS)
Date: 22-05-2015
Abstract: Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor (GPCR) involved in inflammation and metabolism. It is activated through cleavage of its N-terminus by proteases. The new N-terminus functions as a tethered ligand that folds back and intramolecularly activates PAR2, initiating multiple downstream signaling pathways. The only compounds reported to date to inhibit PAR2 activation are of moderate potency. Three structural models for PAR2 have been constructed based on sequence homology with known crystal structures for bovine rhodopsin, human ORL-1 (also called nociceptin/orphanin FQ receptor), and human PAR1. The three PAR2 model structures were compared and used to predict potential interactions with ligands. Virtual screening for ligands using the Chembridge database, and either ORL-1 or PAR1 derived PAR2 models led to identification of eight new small molecule PAR2 antagonists (IC50 10-100 μM). Notably, the most potent compound 1 (IC50 11 μM) was derived from the less homologous template protein, human ORL-1. The results suggest that virtual screening against multiple homology models of the same GPCR can produce structurally erse antagonists and that this may be desirable even when some models have less sequence homology with the target protein.
2,3-Dibromo-2-methyl-5-phenylpentanoic Acid
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M65
Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria
Publisher: American Society for Microbiology
Date: 02-2006
DOI: 10.1128/AAC.50.2.639-648.2006
Abstract: Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.
Tributyl-[(Z)-5-phenyl-2-penten-2-yl]stannane
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M67
Generation and characterization of proteolytically active and highly stable truncated and full-length recombinant West Nile virus NS3
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1016/J.PEP.2006.10.022
Abstract: West Nile virus is a medically significant emerging pathogen for which there is no effective antiviral therapy. The viral protease encoded by NS2B and NS3 is an attractive target for development of an inhibitor and has been the focus of numerous studies. Most have employed recombinant proteases based on an expression strategy we developed which links the essential hydrophilic cofactor domain within NS2B to the NS3 protease domain by a flexible glycine linker. However, autoproteolysis has been a significant problem associated with this construct. The recently resolved crystal structure of the cofactor bound WNV NS3 protease for ex le, was found to be truncated by 18 residues at its N-terminus. In this study, the autocatalytic cleavage site was identified and removed along with nonessential regions of the glycine linker and cofactor domain. In addition, the optimal size of the NS3 protease was defined. Based on this optimized construct, a recombinant protease incorporating the full length of NS3 was also successfully expressed and purified. Somewhat surprisingly, comparative analysis of the proteolytic activity of this recombinant with that of the protease domain alone revealed little influence of the C-terminal two thirds of NS3 on substrate binding. These modifications have yielded highly stable and constrained recombinant proteases, which are more suitable than existing constructs for both activity and structural studies.
[(Z)-5-Phenyl-2-penten-2-yl]mercury Bromide
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M68
Why are there so few Australian chemists on Twitter?
Publisher: Figshare
Date: 2019
[(Z)-5-Phenyl-2-penten-2-yl]mercury Acetate
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M69
Homology Models and Molecular Dynamics of SARS-CoV-2 Coronaviral Protease 3CLpro
Publisher: figshare
Date: 2020
Regioselective synthesis of antiparallel loops on a macrocyclic scaffold constrained by oxazoles and thiazoles
Publisher: American Chemical Society (ACS)
Date: 11-09-2002
DOI: 10.1021/OL026463M
Abstract: The regioselective syntheses and structures are reported for two tris-macrocylic compounds, each possessing two antiparallel loops on a macrocyclic scaffold constrained by two oxazoles and two thiazoles. NMR solution structures show the loops projecting from the same face of the macrocycle. Such molecules are shown to be prototypes for mimicking multiple loops of proteins.[structure: see text]
Homology Models of Coronavirus 2019-nCoV 3CLpro Protease
Publisher: American Chemical Society (ACS)
Date: 05-02-2020
DOI: 10.26434/CHEMRXIV.11637294
Abstract: A regional outbreak of pneumonia in Wuhan, Hubei Province of China in late 2019 was associated with a novel coronavirus. Rapid release of genomic data for the isolated virus enabled the construction of first-generation homology models of the new CoV 3CL sup ro /sup cysteine protease. Whilst the overall viral genome was most closely associated with bat coronaviruses, the main protease is most closely related (96% identity) to SARS CoV protease.
Stereoelectronic Effects on Dienophile Separation Influence the Diels–Alder Synthesis of Molecular Clefts
Publisher: Figshare
Date: 2019
Potent cationic inhibitors of west Nile virus NS2B/NS3 protease with serum stability, cell permeability and antiviral activity
Publisher: American Chemical Society (ACS)
Date: 26-08-2008
DOI: 10.1021/JM800503Y
Abstract: West Nile virus (WNV) has spread rapidly around the globe, efficiently crossing species from migrating birds into humans and other mammals. The viral protease NS2B-NS3 is important for WNV replication and recognizes dibasic substrate sequences common to other flaviviral proteases but different from most mammalian proteases. Potent inhibitors of WNV protease with antiviral activity have been elusive to date. We report the smallest and most potent inhibitors known for this enzyme, cationic tripeptides with nonpeptidic caps at the N-terminus and aldehyde at the C-terminus. One of these, compound 3 ( Ki = 9 nM) is stable in serum (>90% intact after 3 h, 37 degrees C), cell permeable, and shows antiviral activity (IC 50 1.6 microM) without cytotoxicity (IC 50 >400 microM), thereby validating the approach of inhibiting WNV protease to suppress WNV replication.
Towards Arginine Mimetics
Publisher: Figshare
Date: 2019
Homology Models and Molecular Dynamics of SARS-CoV-2 Coronaviral Protease 3CLpro
Publisher: figshare
Date: 2020
2-(Het)aryl-Substituted 7-Azabicyclo[2.2.1]heptane Systems
Publisher: Wiley
Date: 09-1998
DOI: 10.1002/(SICI)1099-0690(199809)1998:9<1997::AID-EJOC1997>3.0.CO;2-A
A Selective and Versatile Synthesis of Substituted Chromones via Addition of Phenols to Dimethyl Acetylenedicarboxylate
Publisher: CSIRO Publishing
Date: 1995
DOI: 10.1071/CH9950677
Abstract: Despite many published syntheses of chromones, none has been reported to be both selective for chromones and tolerant of ring substitution. The addition of substituted phenols to dimethyl acetylenedicarboxylate is now reported as a versatile high yield initial step in a simple three-step synthesis of chromone 2-carboxylic acids. Triethylamine being used to deprotonate the substituted phenol, the addition to dimethyl acetylenedicarboxylate proceeds under mild conditions and tolerates a wide range of functional groups on the phenol. Although not stereoselective, both fumarate and maleate aryloxy products of this addition can then be cyclized, according to a known method, to chromones without contamination by isomeric coumarins. Thus the addition reaction is a valuable component of a versatile and selective synthesis of substituted chromones.
An interaction between the methyltransferase and RNA dependent RNA polymerase domains of the West Nile virus NS5 protein
Publisher: Microbiology Society
Date: 09-2013
Abstract: The flavivirus nonstructural protein 5 (NS5) is a large protein that is structurally conserved among members of the genus, making it an attractive target for antiviral drug development. The protein contains a methyltransferase (MTase) domain and an RNA dependent RNA polymerase (POL) domain. Previous studies with dengue viruses have identified a genetic interaction between residues 46–49 in the αA3-motif in the MTase and residue 512 in POL. These genetic interactions are consistent with structural modelling of these domains in West Nile virus (WNV) NS5 that predict close proximity of these regions of the two domains, and potentially a functional interaction mediated via the αA3-motif. To demonstrate an interaction between the MTase and POL domains of the WNV NS5 protein, we co-expressed affinity-tagged recombinant MTase and POL proteins in human embryonic kidney cells with simian virus 40 large T antigen (HEK293T cells) and performed pulldown assays using an antibody to the flag tag on POL. Western blot analysis with an anti-MTase mAb revealed that the MTase protein was specifically co-immunoprecipitated with POL, providing the first evidence of a specific interaction between these domains. To further assess the role of the αA3 helix in this interaction, selected residues in this motif were mutated in the recombinant MTase and the effect on POL interaction determined by the pulldown assay. These mutations were also introduced into a WNV infectious clone (FLSDX) and the replication properties of these mutant viruses assessed. While none of the αA3 mutations had a significant effect on the MTase–POL association in pulldown assays, suggesting that these residues were not specific to the interaction, an E46L mutation completely abolished virus viability indicating a critical requirement of this residue in replication. Failure to generate compensatory mutations in POL to rescue replication, even after several passages of the transfection supernatant in Vero cells, precluded further conclusion of the role of this residue in the context of MTase–POL interactions.
(E)-3-(2-Methoxyphenyl)-2-butenoic Acid
Publisher: MDPI AG
Date: 06-03-1998
DOI: 10.3390/M73
Structures of peptide agonists for human protease activated receptor 2
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.BMCL.2011.12.029
Abstract: Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor in being self-activated, after pruning of the N-terminus by serine proteases like trypsin and tryptase. Short synthetic peptides corresponding to the newly exposed N-terminal hexapeptide sequence also activate PAR2 on immunoinflammatory, cancer and many normal cell types. (1)H nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopy were used here to search for structural clues to activating mechanisms of the hexapeptide agonists SLIGRL (rat), SLIGKV (human) and the peptidomimetic analogue, 2-furoyl-LIGRLO. Either with a free or acetyl capped N-terminus, these agonist peptides display significant propensity in aprotic (DMSO) or lipidic (water-SDS) solvents for turn-like conformations, which are predicted to be receptor-binding conformations in the transmembrane or loops region of PAR2. These motifs may be valuable for the design of small molecule PAR2 agonists and antagonists as prospective new drugs for regulating inflammatory and proliferative diseases.
Towards Arginine Mimetics
Publisher: Figshare
Date: 2019
Potent Heterocyclic Ligands for Human Complement C3a Receptor
Publisher: American Chemical Society (ACS)
Date: 08-10-2014
DOI: 10.1021/JM500956P
Abstract: The G-protein coupled receptor (C3aR) for human inflammatory protein complement C3a is an important component of immune, inflammatory, and metabolic diseases. A flexible compound (N2-[(2,2-diphenylethoxy)acetyl]-l-arginine, 4), known as a weak C3aR antagonist (IC50 μM), was transformed here into potent agonists (EC50 nM) of human macrophages (Ca(2+) release in HMDM) by incorporating aromatic heterocycles. Antagonists were also identified. A linear correlation between binding affinity for C3aR and calculated hydrogen-bond interaction energy of the heteroatom indicated that its hydrogen-bonding capacity influenced ligand affinity and function mediated by C3aR. Hydrogen-bond accepting heterocycles (e.g., imidazole) conferred the highest affinity and agonist potency (e.g., 21, EC50 24 nM, Ca(2+), HMDM) with comparable efficacy and immunostimulatory activity as that of C3a in activating human macrophages (Ca(2+), IL1β, TNFα, CCL3). These potent and selective modulators of C3aR, inactivated by a C3aR antagonist, are stable C3a surrogates for interrogating roles for C3aR in physiology and disease.
Current Status of Virtual Screening as Analysed by Target Class
Publisher: Bentham Science Publishers Ltd.
Date: 2006
DOI: 10.2174/157340606775197750
Abstract: In silico virtual screening for drug discovery has become a hot topic in medicinal chemistry research during the last 5 years, growing from a largely academic pursuit concerned principally with validating the methods used, to a major early-stage technique for lead discovery in the pharmaceutical industry. In this review we highlight a few recent successes in ligand docking associated with virtual screening, paying particular attention to four major target classes of pharmaceutical interest (G Protein-Coupled receptors, nuclear hormone receptors, kinases, proteases). We also discuss some emerging trends in the field, some common limitations, and how they are being overcome.
Flaviviral virus proteases. What do crystal structures and homology models actually tell us?
Publisher: Figshare
Date: 2019
Synthesis and cannabinoid activity of a variety of 2,3-substituted 1-benzo[b]thiophen derivatives and 2,3-substituted benzofuran: Novel agonists for the CB1 receptor
Publisher: CSIRO Publishing
Date: 2008
DOI: 10.1071/CH07412
Abstract: An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB1 agonists. It is hoped that compounds of this type will have clinical utility in pain control and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of several classes of 1-benzo[b]thiophen and benzofuran derivatives as novel CB1 agonists. We have discovered a novel series of compounds, which contain a 1-benzo[b]thiophen or a benzofuran group as the central aromatic group. Our investigation of this series of compounds has enhanced our understanding of the importance of binding sites within the CB1 receptor for favourable CB1 potency. Our understanding of these factors allowed us to modify the structure of a 1-benzothiophen derivative and improve its potency at the CB1 receptor.
Flaviviral virus proteases. What do crystal structures and homology models actually tell us?
Publisher: Figshare
Date: 2019
Some design implications of X-ray crystal structures of SARS-CoV-2 3CLpro
Publisher: figshare
Date: 2020
Cycloadditions of isobenzofuran to a constrained template bearing neighboring dienophiles
Publisher: Wiley
Date: 05-05-2003
Abstract: A high yielding synthesis of the pentacyclic diene-dione 1 has enabled investigation of its reactivity as a double dienophile in Diels-Alder [4+2] cycloadditions with isobenzofuran, leading to novel and highly symmetrical three-sided cavitands 3 and 4.
Homology Models of the Papain-Like Protease PLpro from Coronavirus 2019-nCoV
Publisher: American Chemical Society (ACS)
Date: 04-02-2020
DOI: 10.26434/CHEMRXIV.11799705
Abstract: The December 2019 outbreak of pneumonia in Wuhan, Hubei Province of China was rapidly linked to a novel coronavirus 2019-nCoV. The rapid spread and severity of the virus has led the World Health Organization to declare it a Public Health Emergency of International Concern. We recently described the first homology models of the main 3CL protease from 2019-nCoV, and now present models of the other viral protease, the papain-like protease or PLpro. Whilst the overall viral genome is most closely associated with bat coronaviruses, no bat PLpro crystal structures are known. Wuhan 2019-nCoV PLpro is most closely related to a bat coronavirus PLpro (97% identity), then SARS (80 %) and MERS (29%) and the most promising models presented here are prepared from SARS crystal structure templates.
ChemInform Abstract: Synthesis and Cannabinoid Activity of 1‐Substituted‐indole‐3‐oxadiazole Derivatives: Novel Agonists for the CB1 Receptor.
Publisher: Wiley
Date: 04-07-2008
In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.ANTIVIRAL.2009.09.007
Abstract: The flaviviruses comprise a large group of related viruses, many of which pose a significant global human health threat, most notably the dengue viruses (DENV), West Nile virus (WNV) and yellow fever virus (YFV). Flaviviruses enter host cells via fusion of the viral and cellular membranes, a process mediated by the major viral envelope protein E as it undergoes a low pH induced conformational change in the endosomal compartment of the host cell. This essential entry stage in the flavivirus life cycle provides an attractive target for the development of antiviral agents. We performed an in silico docking screen of the Maybridge chemical database within a previously described ligand binding pocket in the dengue E protein structure that is thought to play a key role in the conformational transitions that lead to membrane fusion. The biological activity of selected compounds identified from this screen revealed low micromolar antiviral potency against dengue virus for two of the compounds. Our results also provide the first evidence that compounds selected to bind to this ligand binding site on the flavivirus E protein abrogate fusion activity. Interestingly, one of these compounds also has antiviral activity against both WNV (kunjin strain) and YFV.
Mutagenesis of the West Nile virus NS2B cofactor domain reveals two regions essential for protease activity
Publisher: Microbiology Society
Date: 04-2008
Abstract: The flavivirus NS2B/NS3 protease has received considerable attention as a target for the development of antiviral compounds. While substrate based inhibitors have been the primary focus to date, an approach focussing on NS2B cofactor displacement could prove to be an effective alternative. To understand better the role of the NS2B cofactor in protease activation, we conducted an alanine mutagenesis screen throughout the 42-residue central cofactor domain (NS2B 51–92 ) of West Nile virus (WNV). Two sites critical for proteolytic activity were identified (NS2B 59–62 and NS2B 75–87 ), where the majority of substitutions were found to significantly decrease proteolytic activity of a recombinant WNV NS2B/NS3 protease. These findings provide mechanistic insights into the structural and functional role that the cofactor may play in the substrate-bound and free protease complexes as well as providing novel sites for targeting new antiviral inhibitors.
Identification of crotonyl glycine in sheep urine of sheep subjected to 48 h road transport using RP-HPLC, NMR and ESI-MS
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.JPBA.2012.04.028
Abstract: Thousands of metabolites are excreted in urine, and potentially can be detected in NMR spectra. Currently, NMR spectral information for about one thousand metabolites has been deposited in publicly available sources, limiting the identification of chemical compounds that are potential biomarkers for clinical and subclinical applications. This study reports the identification of crotonyl glycine, one of the key metabolites detected by ¹H NMR as excreted in the urine of sheep after 48 h road transport and during the subsequent 72 h recovery period. This metabolite was important in separating the metabolic responses as expressed in the urine from animals undergoing shorter road transport treatments. At the time of the metabonomic analysis, the NMR signals from this metabolite were designated as unassigned as no match was found in public databases or the literature. Selected sheep urine s les containing the metabolite were resolved by reversed phase HPLC reducing the s le complexity. Subsequent ¹H NMR spectra of the collected fractions revealed that the unknown metabolite was present in a single HPLC fraction. High-resolution 1D and 2D ¹H NMR spectra of this fraction followed by mass determination of the parent ion and its fragments by nanoESI-TOF-MS/MS revealed the identity of the compound as crotonyl glycine (N-but-(E)-2-enoyl glycine). The HPLC fraction was subsequently spiked with synthetic crotonyl glycine which confirmed identification.
Virtual Screening of Peptide and Peptidomimetic Fragments Targeted to Inhibit Bacterial Dithiol Oxidase DsbA
Publisher: Public Library of Science (PLoS)
Date: 30-07-2015
Potent Cyclic Antagonists of the Complement C5a Receptor on Human Polymorphonuclear Leukocytes. Relationships between Structures and Activity
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 25-03-2004
DOI: 10.1124/MOL.65.4.868
Identification and characterization of bi-thiazole-2,2'-diamines as kinase inhibitory scaffolds.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.BBAPAP.2013.02.001
Abstract: Based on bioinformatics interrogation of the genome, >500 mammalian protein kinases can be clustered within seven different groups. Of these kinases, the mitogen-activated protein kinase (MAPK) family forms part of the CMGC group of serine/threonine kinases that includes extracellular signal regulated kinases (ERKs), cJun N-terminal kinases (JNKs), and p38 MAPKs. With the JNKs considered attractive targets in the treatment of pathologies including diabetes and stroke, efforts have been directed to the discovery of new JNK inhibitory molecules that can be further developed as new therapeutics. Capitalizing on our biochemical understanding of JNK, we performed in silico screens of commercially available chemical databases to identify JNK1-interacting compounds and tested their in vitro JNK inhibitory activity. With in vitro and cell culture studies, we showed that the compound, 4'-methyl-N(2)-3-pyridinyl-4,5'-bi-1,3-thiazole-2,2'-diamine (JNK Docking (JD) compound 123, but not the related compound (4'-methyl-N~2~-(6-methyl-2-pyridinyl)-4,5'-bi-1,3-thiazole-2,2'-diamine (JD124), inhibited JNK1 activity towards a range of substrates. Molecular docking, saturation transfer difference NMR experiments and enzyme kinetic analyses revealed both ATP- and substrate-competitive inhibition of JNK by JD123. In characterizing JD123 further, we noted its ATP-competitive inhibition of the related p38-γ MAPK, but not ERK1, ERK2, or p38-α, p38-β or p38-δ. Further screening of a broad panel of kinases using 10μM JD123, identified inhibition of kinases including protein kinase Bβ (PKBβ/Aktβ). Appropriately modified thiazole diamines, as typified by JD123, thus provide a new chemical scaffold for development of inhibitors for the JNK and p38-γ MAPKs as well as other kinases that are also potential therapeutic targets such as PKBβ/Aktβ.
Some design implications of X-ray crystal structures of SARS-CoV-2 3CLpro
Publisher: figshare
Date: 2020
Stereoelectronic Effects on Dienophile Separation Influence the Diels–Alder Synthesis of Molecular Clefts
Publisher: Wiley
Date: 04-12-2017
Stereoelectronic Effects on Dienophile Separation Influence the Diels–Alder Synthesis of Molecular Clefts
Publisher: Figshare
Date: 2019
Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed
Publisher: American Chemical Society (ACS)
Date: 07-08-2014
DOI: 10.1021/ML5002823
Activity of Recombinant Dengue 2 Virus NS3 Protease in the Presence of a Truncated NS2B Co-factor, Small Peptide Substrates, and Inhibitors
Publisher: Elsevier BV
Date: 12-2001
Enzymatic characterization and homology model of a catalytically active recombinant West Nile Virus NS3 protease
Publisher: Elsevier BV
Date: 11-2004
Related Organisations
Technische Universität Clausthal Fakultät Für Natur- Und Materialwissenschaften
Location: Germany
Related Funding Activities
(Chemi–biology Computational Platform For Lead Discovery In Infectious Disease)
Start Date: 2012
End Date: 2012
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE120100071
Start Date: 03-2012
End Date: 03-2014
Amount: $290,000.00
Funder: Australian Research Council
View Funded Activity