ORCID Profile
0000-0002-3600-0497
Current Organisations
The University of Edinburgh
,
University of Leeds
,
University Of Strathclyde
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Publisher: Elsevier
Date: 2015
DOI: 10.1016/BS.VH.2014.10.001
Abstract: Nociceptin (orphanin FQ) is a 17-residue neuropeptide hormone with roles in both nociception and analgesia. It is an opioid-like peptide that binds to and activates the G-protein-coupled receptor opioid receptor-like-1 (ORL-1, NOP, orphanin FQ receptor, kappa-type 3 opioid receptor) on central and peripheral nervous tissue, without activating classic delta-, kappa-, or mu-opioid receptors or being inhibited by the classic opioid antagonist naloxone. The three-dimensional structure of ORL-1 was recently published, and the activation mechanism is believed to involve capture by ORL-1 of the high-affinity binding, prohelical C-terminus. This likely anchors the receptor-activating N-terminus of nociception nearby for insertion in the membrane-spanning helices of ORL-1. In search of higher agonist potency, two lysine and two aspartate residues were strategically incorporated into the receptor-binding C-terminus of the nociceptin sequence and two Lys(i)→Asp(i+4) side chain-side chain condensations were used to generate lactam cross-links that constrained nociceptin into a highly stable α-helix in water. A cell-based assay was developed using natively expressed ORL-1 receptors on mouse neuroblastoma cells to measure phosphorylated ERK as a reporter of agonist-induced receptor activation and intracellular signaling. Agonist activity was increased up to 20-fold over native nociceptin using a combination of this helix-inducing strategy and other amino acid modifications. An NMR-derived three-dimensional solution structure is described for a potent ORL-1 agonist derived from nociceptin, along with structure-activity relationships leading to the most potent known α-helical ORL-1 agonist (EC₅₀ 40 pM, pERK, Neuro-2a cells) and antagonist (IC₅₀ 7 nM, pERK, Neuro-2a cells). These α-helix-constrained mimetics of nociceptin(1-17) had enhanced serum stability relative to unconstrained peptide analogues and nociceptin itself, were not cytotoxic, and displayed potent thermal analgesic and antianalgesic properties in rats (ED₅₀ 70 pmol, IC₅₀ 10 nmol, s.c.), suggesting promising uses in vivo for the treatment of pain and other ORL-1-mediated responses.
Publisher: American Chemical Society (ACS)
Date: 07-2022
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0CC02361B
Abstract: Activity-directed synthesis harnessing 220 Pd-catalysed microscale reactions enabled expansion of a series of quinazolinone antibacterials.
Publisher: Wiley
Date: 2019
DOI: 10.1111/EMR.12352
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.
Publisher: American Chemical Society (ACS)
Date: 24-03-2017
DOI: 10.1021/ACS.JMEDCHEM.7B00423
Abstract: The chemical space explored in drug discovery programs is restricted by a narrow reaction toolkit and the frequent failure of even these reactions with polar and functionalized substrates. Recently, high-throughput reaction optimization has been integrated into discovery workflows, thereby increasing the value of specific reaction classes in the toolkit. It is likely that high-throughput experimentation will enable expansion of the synthetic chemistry that is widely exploited in discovery, thereby increasing innovation in medicinal chemistry.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9MD00085B
Abstract: The structural ersity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors was expanded by harnessing erse building blocks that had been prepared via a unified lead-oriented synthetic approach.
Publisher: American Chemical Society (ACS)
Date: 18-03-2016
Abstract: An efficient synthesis of sulfonyl carbamates and sulfonyl ureas from sulfonyl azides employing a palladium-catalyzed carbonylation protocol has been developed. Using a two-chamber system, sulfonyl azides, PdCl2, and CO gas, released ex situ from Mo(CO)6, were assembled to generate sulfonyl isocyanates in situ, and alcohols and aryl amines were exploited as nucleophiles to afford a broad range of sulfonyl carbamates and sulfonyl ureas. A protocol for the direct formation of substituted sulfonamides from sulfonyl azides and amines via nucleophilic substitution was also developed.
Publisher: Magnolia Press
Date: 04-03-2019
DOI: 10.11646/ZOOTAXA.4564.1.6
Abstract: The taxonomic status and systematic nomenclature of the Australian dingo remain contentious, resulting in decades of inconsistent applications in the scientific literature and in policy. Prompted by a recent publication calling for dingoes to be considered taxonomically as domestic dogs (Jackson et al. 2017, Zootaxa 4317, 201-224), we review the issues of the taxonomy applied to canids, and summarise the main differences between dingoes and other canids. We conclude that (1) the Australian dingo is a geographically isolated (allopatric) species from all other Canis, and is genetically, phenotypically, ecologically, and behaviourally distinct and (2) the dingo appears largely devoid of many of the signs of domestication, including surviving largely as a wild animal in Australia for millennia. The case of defining dingo taxonomy provides a quintessential ex le of the disagreements between species concepts (e.g., biological, phylogenetic, ecological, morphological). Applying the biological species concept sensu stricto to the dingo as suggested by Jackson et al. (2017) and consistently across the Canidae would lead to an aggregation of all Canis populations, implying for ex le that dogs and wolves are the same species. Such an aggregation would have substantial implications for taxonomic clarity, biological research, and wildlife conservation. Any changes to the current nomen of the dingo (currently Canis dingo Meyer, 1793), must therefore offer a strong, evidence-based argument in favour of it being recognised as a subspecies of Canis lupus Linnaeus, 1758, or as Canis familiaris Linnaeus, 1758, and a successful application to the International Commission for Zoological Nomenclature - neither of which can be adequately supported. Although there are many species concepts, the sum of the evidence presented in this paper affirms the classification of the dingo as a distinct taxon, namely Canis dingo.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB01064H
Abstract: A rapid, efficient and high-yielding synthesis of 11 C-cyanobenzamides, including novel analogs of various drug molecules, is described.
Publisher: Wiley
Date: 16-08-2017
Publisher: American Chemical Society (ACS)
Date: 10-11-2010
DOI: 10.1021/JM101139F
Abstract: The nociceptin opioid peptide receptor (NOP, NOR, ORL-1) is a GPCR that recognizes nociceptin, a 17-residue peptide hormone. Nociceptin regulates pain transmission, learning, memory, anxiety, locomotion, cardiovascular and respiratory stress, food intake, and immunity. Nociceptin was constrained using an optimized helix-inducing cyclization strategy to produce the most potent NOP agonist (EC50 = 40 pM) and antagonist (IC50 = 7.5 nM) known. Alpha helical structures were measured in water by CD and 2D (1)H NMR spectroscopy. Agonist and antagonist potencies, evaluated by ERK phosphorylation in mouse neuroblastoma cells natively expressing NOR, increased 20-fold and 5-fold, respectively, over nociceptin. Helix-constrained peptides with key amino acid substitutions had much higher in vitro activity, serum stability, and thermal analgesic activity in mice, without cytotoxicity. The most potent agonist increased hot plate contact time from seconds up to 60 min the antagonist prevented this effect. Such helix-constrained peptides may be valuable physiological probes and therapeutics for treating some forms of pain.
Publisher: Wiley
Date: 07-06-2016
Abstract: A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac-Ir(ppy)3 -catalyzed radical aminocarbonylation protocol has been developed. Using a two-chambered system, alkyl iodides, fac-Ir(ppy)3 , amines, reductants, and CO gas (released ex situ from Mo(CO)6 ), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.
Publisher: Wiley
Date: 31-05-2016
Publisher: Wiley
Date: 2019
DOI: 10.1111/EMR.12357
Publisher: Royal Society of Chemistry (RSC)
Date: 2008
DOI: 10.1039/B806391E
Abstract: A structural model for the active site of phosphoesterases, enzymes that degrade organophosphate neurotoxins, has been synthesised. The ligand [2-((2-hydroxy-3-(((2-hydroxyethyl)(pyridin-2-ylmethyl)amino)methyl)-5-methylbenzyl)(pyridin-2-ylmethyl)amino)acetic acid] (H(3)L1) and two Zn(ii) complexes have been prepared and characterised as [Zn(2)(HL1)(CH(3)COO)](PF(6)).H(2)O and Li[Zn(2)(HL1)](4)(PO(4))(2)(PF(6))(3).(CH(3)OH). The ligand (H(3)L1) and complex [Zn(2)(HL1)(CH(3)COO)](PF(6)).H(2)O were characterised through (1)H NMR, (13)C NMR, mass spectroscopy and microanalysis. The X-ray crystal structure of Li[Zn(2)(HL1)](4)(PO(4))(2)(PF(6))(3).(CH(3)OH) revealed a tetramer of dinuclear complexes, bridged by two phosphate molecules and bifurcating acetic acid arms. Functional studies of the zinc complex with the substrate bis(4-nitrophenyl)phosphate (bNPP) determined the complex with HL1(2-) to be a competent catalyst with k(cat) = 1.26 +/- 0.06 x 10(-6) s(-1).
Publisher: Wiley
Date: 07-2016
Publisher: Wiley
Date: 07-09-2017
Publisher: Wiley
Date: 06-09-2017
Publisher: Springer Science and Business Media LLC
Date: 27-07-2018
Publisher: CSIRO Publishing
Date: 2018
DOI: 10.1071/PC18024
Abstract: Since European occupation of Australia, human activities have caused the dramatic decline and sometimes extinction of many of the continent’s unique species. Here we provide a comprehensive review of threats to species listed as threatened under Australia’s Environment Protection and Bio ersity Conservation Act 1999. Following accepted global categories of threat, we find that invasive species affect the largest number of listed species (1257 species, or 82% of all threatened species) ecosystem modifications (e.g. fire) (74% of listed species) and agricultural activity (57%) are also important. The ranking of threats was largely consistent across taxonomic groups and the degree of species’ endangerment. These results were significantly different (P& .01) from recent analyses of threats to threatened species globally, which highlighted overexploitation, agriculture and urban development as major causes of decline. Australia is distinct not only in the bio ersity it contains but also in the extent and mixture of processes that threaten the survival of these species. Notably, the IUCN threat classification scheme separates the numerous threats (e.g. urban development, agriculture, mining) that cause habitat loss, fragmentation and degradation, hence further research is required to quantify the net impact of these types of habitat change. We provide feasible suggestions for a more coordinated national approach to threatened species conservation, which could provide decision makers and managers at all levels with improved resources and information on threats and management. Adequate policy, legislative support and funding are critical for ensuring that on-ground management is successful in halting the decline of Australia’s threatened species.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Shiao Chow.