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Browsing Chemistry publications by Author "Abell, A.D."
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Item Metadata only Designer D-peptides targeting the N-terminal region of α-synuclein to prevent parkinsonian-associated fibrilization and cytotoxicity(Elsevier BV, 2022) Horsley, J.R.; Jovcevski, B.; Pukala, T.L.; Abell, A.D.The deposition of α-synuclein (αS) aggregates in the gut and the brain is ever present in cases of Parkinson’s disease. While the central non-amyloidogenic-component (NAC) region of αS plays a critical role in fibrilization, recent studies have identified a specific sequence from within the N-terminal region (NTR, residues 36–42) as a key modulator of αS fibrilization. Due to the lack of effective therapeutics which specifically target αS aggregates, we have developed a strategy to prevent the aggregation and subsequent toxicity attributed to αS fibrilization utilizing NTR targeting peptides. In this study, L- and D-isoforms of a hexa- (VAQKTV-Aib, 77–82 NAC) and heptapeptide (GVLYVGS-Aib, 36–42 NTR) containing a self-recognition component unique to αS, as well as a Cterminal disruption element, were synthesized to target primary sequence regions of αS that modulate fibrilization. The D-peptide that targets the NTR (NTR-TP-D) was shown by ThT fluorescence assays and TEM to be the most effective at preventing fibril formation and elongation, as well as increasing the abundance of soluble monomeric αS. In addition, NTR-TP-D alters the conformation of destabilised monomers into a less aggregationprone state and reduces the hydrophobicity of αS fibrils via fibril remodelling. Furthermore, both NTR-TP isoforms alleviate the cytotoxic effects of αS aggregates in both Neuro-2a and Caco-2 cells. Together, this study highlights how targeting the NTR of αS using D-isoform peptide inhibitors may effectively combat the deleterious effects of αS fibrilization and paves the way for future drug design to utilise such an approach to treat Parkinson’s disease.Item Metadata only Enhancing forbidden light propagation in nanoporous anodic alumina gradient-index filters by alcohol additives(American Chemical Society (ACS), 2020) Lim, S.Y.; Law, C.S.; Jiang, L.; Acosta, L.K.; Bachhuka, A.; Marsal, L.F.; Abell, A.D.; Santos, A.A comprehensive study on structural and optical engineering of high-quality nanoporous anodic alumina gradient-index filters (NAA-GIFs) by selective addition of alcohols to the anodizing acid electrolyte is presented. Analysis of the combined effect of type (methanol, ethanol, isopropanol, and ethylene glycol) and concentration (from 10 to 70 vol %) of alcohol additives in sulfuric acid electrolytes on the optical features of the characteristic photonic stopband of NAA-GIFs—central wavelength, full width at half maximum, intensity, and quality factor—allows us to elucidate the most optimal fabrication conditions to produce high-quality NAA-GIFs by sinusoidal pulse anodization under mild conditions. Comprehensive electrochemical, structural, optical, and chemical analyses demonstrate that a suitable selection of type and concentration of the alcohol additive is critical in controlling the quality of forbidden light propagation within these photonic crystal (PC) structures. Particularly, NAA-GIFs produced by sinusoidal pulse anodization in the sulfuric acid electrolyte modified with 40 vol % methanol achieve an outstanding quality factor of ∼58 (32–54% superior than that of other alcohol additives). Our findings indicate that a combination of anodic oxide growth rate and suppressing dissolution efficiencies, mildly branched nanoporous structure, and incorporation of carbon-containing impurities into the structure of NAA-GIFs are critical factors in enhancing light-forbidding quality of these NAA-based PCs. Our results advance the understanding of structural engineering of NAA-PCs by dynamic modification of the input anodization profile under optimal electrolyte conditions.Item Metadata only Exploiting conformationally gated electron transfer in self-assembled azobenzene-containing cyclic peptides using light(Elsevier, 2021) Horsley, J.R.; Wang, X.; Yu, J.; Abell, A.D.An azobenzene photoswitch was incorporated into a peptide as a side chain constraint to allow interconversion between two photostationary states (PSS) comprising well-defined β-strand geometry. The peptide was covalently attached to a carbon electrode with a terminal redox-active ferrocene moiety for electrochemical interrogation of each PSS. While readily switching in solution, the increased molar volume of the cis isomer is believed to hinder the conformational change in the peptide on a self-assembled monolayer (SAM). The introduction of diluents to increase the distance between chromophores reduced these steric effects to provide on/off switching between the two photostationary states of the peptide on the SAM using alternative irradiation of UV and visible light. The structural and electronic properties of each PSS differed significantly, enabling this gated approach to exploit changes in the molecular structure that provide opportunities for the design and development of future photoswitchable peptide-based SAMs with controllable electronic functions, for applications in areas such as sensing and molecular electronics.Item Open Access Exploring Photoswitchable Binding Interactions with Small Molecule- and Peptide-Based Inhibitors of Trypsin(Wiley, 2023) Palasis, K.; Peddie, V.; Turner, D.; Zhang, X.; Yu, J.; Abell, A.D.The ability to photochemically activate a drug, both when and where needed, requires optimisation of the difference in biological activity between each isomeric state. As a step to this goal, we report small molecule and peptide-based inhibitors of the same protease - trypsin - to better understand how photoswitchable drugs interact with their biological target. The best peptidic inhibitor displayed a >5-fold difference in inhibitory activity between isomeric states, whereas the best small molecule inhibitor only showed a 3.4-fold difference. Docking and molecular modelling suggests this result is due to a large change in 3D structure in the key binding residues of the peptidic inhibitor upon isomerisation, which is not observed for the small molecule inhibitor. Hence, we demonstrate that significant structural changes in critical binding motifs upon irradiation are essential for maximising the difference in biological activity between isomeric states. This is an important consideration in the design of future photoswitchable drugs for clinical applications.Item Metadata only Inhibition of Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS): toward next-generation antituberculosis agents(American Chemical Society, 2021) Schumann, N.C.; Lee, K.J.; Thompson, A.P.; Salaemae, W.; Pederick, J.L.; Avery, T.; Gaiser, B.I.; Hodgkinson-Bean, J.; Booker, G.W.; Polyak, S.W.; Bruning, J.B.; Wegener, K.L.; Abell, A.D.Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, M. tuberculosis. Here, we report a binder of MtDTBS, cyclopentylacetic acid 2 (K(D) = 3.4 ± 0.4 mM), identified viain silico screening. X-ray crystallography showed that 2 binds in the 7,8-diaminopelargonic acid (DAPA) pocket of MtDTBS. Appending an acidic group to the para-position of the aromatic ring of the scaffold revealed compounds 4c and 4d as more potent binders, with K(D) = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder (K(D) = 57 ± 5 nM) and inhibitor (Ki = 5 ± 1 μM) of MtDTBS. Our findings highlight the first reported inhibitors of MtDTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.Item Metadata only Mechanism of acetal cleavage with methylmagnesium iodide(CSIRO Publishing, 1985) Abell, A.D.; Massywestropp, R.A.The reaction of methylmagnesium iodide with methyl (1R,3S,5R)-1-(furan- 3′-yl)-5-methyl-2,8-dioxabicyclo[3.2.1]octane-3-carboxylate (2) gives products arising from regioselective carbon-oxygen bond fission and intermolecular transfer of the methyl group of the Grignard reagent to the intermediate oxocarbonium ion, in addition to the usual tertiary alcohol.Item Metadata only Nanoporous photonic crystals with tailored surface chemistry for ionic copper sensing(Royal Society of Chemistry, 2019) Eckstein,; Law, C.S.; Lim, S.Y.; Kaur, S.; Kumeria, T.; Ferré-Borrull, J.; Abell, A.D.; Marsal, L.F.; Santos, A.We present a study on optical and surface chemistry engineering of nanoporous photonic crystals as sensing platforms for detection of ionic copper. The optical sensing system combines glutaraldehyde-crosslinked double-layered polyethyleneimine (PEI-GA-PEI)-functionalized nanoporous anodic alumina gradient-index filters (NAA-GIFs) with reflection spectroscopy for label-free, selective detection of ionic copper in water matrices. The spectral position of the photonic stopband (PSB) of PEI-GA-PEI-functionalized NAA-GIFs is tuned across the visible-NIR spectral region to assess the impact of this optical parameter on the sensing performance of the system. Spectral shifts in the characteristic PSB (ΔλPSB) of PEI-GA-PEI-functionalized NAA-GIFs upon exposure to analytical solutions of ionic copper are used as a sensing parameter. Shifts in ΔλPSB of these photonic crystals are monitored in real-time under dynamic flow conditions. Calibration of the sensing system with analytical solutions of ionic copper from 0.1 to 100 mM shows a dual sensing regime, at low (from 1 to 10 mM) and high (from 10 to 100 mM) concentrations, which is associated with conformational changes of the PEI-GA-PEI functional layer. The binding mechanism of Cu2+ in PEI-GA-PEI-modified NAA-GIFs follows a Freundlich isotherm model. The performance of the PEI-GA-PEI-NAA-GIFs for real-life applications is demonstrated using environmental water. The system shows excellent correlation in both environmental and analytical water solutions. This study provides new opportunities to engineer portable optical sensing systems with tailor-designed features to detect ionic copper for environmental applications.Item Open Access Photoswitchable peptide-based ‘on-off’ biosensor for electrochemical detection and control of protein-protein interactions(Elsevier, 2018) Horsley, J.R.; Yu, J.; Wegener, K.L.; Hoppmann, C.; Rück-Braun, K.; Abell, A.D.Neuronal nitric oxide synthase (nNOS) is an enzyme responsible for catalyzing the production of the crucial cellular signalling molecule, nitric oxide (NO), through its interaction with the PDZ domain of α-syntrophin protein. In this study, a novel light-driven photoswitchable peptide-based biosensor, modelled on the nNOS β-finger, is used to detect and control its interaction with α-syntrophin. An azobenzene photoswitch incorporated into the peptide backbone allows reversible switching between a trans photostationary state devoid of secondary structure, and a cis photostationary state possessing a well-defined antiparallel β-strand geometry, as revealed by molecular modelling. Electrochemical impedance spectroscopy (EIS) is used to successfully detect the interaction between the gold electrode bound peptide in its cis photostationary state and a wide range of concentrations of α-syntrophin protein, highlighting both the qualitative and quantitative properties of the sensor. Furthermore, EIS demonstrates that the probe in its random trans photostationary state does not bind to the target protein. The effectiveness of the biosensor is further endorsed by the high thermal stability of the photostationary state of the cis-isomer, and the ability to actively control biomolecular interactions using light. This approach allows detection and control of binding to yield a regenerable on-off biosensor.Item Metadata only Protein detection enabled using functionalised silk-binding peptides on a silk-coated optical fibre(Royal Society of Chemistry, 2021) Capon, P.K.; Horsfall, A.J.; Li, J.; Schartner, E.P.; Khalid, A.; Purdey, M.S.; McLaughlin, R.A.; Abell, A.D.We present a new coating procedure to prepare optical fibre sensors suitable for use with protein analytes. We demonstrate this through the detection of AlexaFluor-532 tagged streptavidin by its binding to D-biotin that is functionalised onto an optical fibre, via incorporation in a silk fibroin fibre coating. The D-biotin was covalently attached to a silk-binding peptide to provide SBP–biotin, which adheres the D-biotin to the silk-coated fibre tip. These optical fibre probes were prepared by two methods. The first involves dip-coating the fibre tip into a mixture of silk fibroin and SBP–biotin, which distributes the SBP–biotin throughout the silk coating (method A). The second method uses two steps, where the fibre is first dip-coated in silk only, then SBP–biotin added in a second dip-coating step. This isolates SBP–biotin to the outer surface of the silk layer (method B). A series of fluorescence measurements revealed that only the surface bound SBP–biotin detects streptavidin with a detection limit of 15 μg mL−1. The fibre coatings are stable to repeated washing and long-term exposure to water. Formation of silk coatings on fibres using commercial aqueous silk fibroin was found to be inhibited by a lithium concentration of 200 ppm, as determined by atomic absorption spectroscopy. This was reduced to less than 20 ppm by dialysis against water, and was found to successfully form a coating on optical fibres.Item Metadata only Rearrangement of freelingyne with base(CSIRO Publishing, 1985) Abell, A.D.; Massywestropp, R.A.; Reynolds, G.D.Treatment of freelingyne (1) with sodium hydroxide in aqueous methanol gives the rearranged acid (2a).Item Metadata only Regioselective bond cleavage and coordination effects in the reduction of some acetals with lithium in ammonia(Pergamon Press, 1985) Abell, A.D.; Massywestropp, R.A.Some benzylic-type acetals possessing the 2,8-dioxa-bicyclo [3.2.1]octane ring system are cleaved in a regioselective manner when treated with lithium in ammonia. The results from various reductions implicate coordination of lithium as a significant factor involved in reduction mechanisms.Item Metadata only Role of spectral resonance features and surface chemistry in the optical sensitivity of light-confining nanoporous photonic crystals(American Chemical Society, 2021) Acosta, L.K.; Law, S.; Lim, S.Y.; Abell, A.D.; Marsal, L.F.; Santos, A.Nanoporous anodic alumina optical microcavities (NAA-μQVs) with spectrally tunable resonance band and surface chemistry are used as model light-confining photonic crystal (PC) platforms to elucidate the combined effect of spectral light confinement features and surface chemistry on optical sensitivity. These model nanoporous PCs show well-resolved, spectrally tunable resonance bands (RBs), the central wavelength of which is engineered from ∼400 to 800 nm by the period of the input anodization profile. The optical sensitivity of the as-produced (hydrophilic) and dichlorodimethylsilane-functionalized (hydrophobic) NAA-μQVs is studied by monitoring dynamic spectral shifts of their RB upon infiltration with organic- and aqueous-based analytical solutions of equally varying refractive index, from 1.333 to 1.345 RIU. Our findings demonstrate that hydrophilic NAA-μQVs show ∼81 and 35% superior sensitivity to their hydrophobic counterparts for organic- and aqueous-based analytical solutions, respectively. Interestingly, the sensitivity of hydrophilic NAA-μQVs per unit of spectral shift is more than 3-fold higher in organic than in aqueous matrices upon equal change of refractive index, with values of 0.347 ± 0.002 and 0.109 ± 0.001 (nm RIU-1) nm-1, respectively. Conversely, hydrophobic NAA-μQVs are found to be slightly more sensitive toward changes of refractive index in aqueous medium, with sensitivities of 0.072 ± 0.002 and 0.066 ± 0.006 (nm RIU-1) nm-1 in water- and organic-based analytical solutions, respectively. Our advances provide insights into critical factors determining optical sensitivity in light-confining nanoporous PC structures, with implications across optical sensing applications, and other photonic technologies.Item Metadata only Smart Wearable Patches Using Light-Controlled Activation and Delivery of Photoswitchable Antimicrobial Peptides(Wiley, 2023) Kalyvas, J.T.; Marina, P.F.; Stachura, D.L.; Horsley, J.; Abell, A.D.A novel strategy to treat Staphylococcus aureus (S. aureus) skin infections is presented, where UV light is used to facilitate concomitant light-controlled activation and delivery of an antimicrobial therapeutic agent. Specifically, a new photoswitchable gramicidin S analogue was immobilized onto a polymeric wearable patch via a photocleavable linker that undergoes photolysis at the same wavelength of light required for activation of the peptide. Unlike toxic gramicidin S, the liberated active photoswitchable peptide exhibits antimicrobial activity against S. aureus while being ostensibly non-haemolytic to red blood cells. Moreover, irradiation with visible light switches off the antimicrobial properties of the peptide within seconds, presenting an ideal strategy to regulate antibiotic activity for localized bacterial infections with the potential to mitigate resistance.Item Metadata only Synthesis and X-ray crystallographic structure of leucine-phenylalanyl succinimide-based pseudopeptides(American Chemical Society, 1997) Abell, A.D.; Oldham, M.D.Item Metadata only Targeting PCNA with peptide mimetics for therapeutic purposes(Wiley, 2020) Horsfall, A.J.; Abell, A.D.; Bruning, J.Proliferating cell nuclear antigen (PCNA) is an excellent inhibition target to shut down highly proliferative cells and thereby develop a broad‐spectrum cancer therapeutic. It interacts with a wide variety of proteins through a conserved motif referred to as the PCNA‐interacting protein (PIP) box. There is large sequence diversity between high‐affinity PCNA binding partners, but with conservation of the binding structure - a well‐defined 3₁₀‐helix. Herein, all current PIP‐box peptides crystallised with human PCNA are collated to reveal common trends between binding structure and affinity. Key intra‐ and intermolecular hydrogen‐bonding networks that stabilise the 3₁₀‐helix of PIP‐box partners are highlighted and related back to the canonical PIP‐box motif. High correlation with the canonical PIP‐box sequence does not directly afford high affinity. Instead, we summarise key interactions that stabilise the binding structure that leads to enhanced PCNA binding affinity. These interactions also implicate the “non‐conserved” residues within the PIP‐box that have previously been overlooked. Such insights will allow a more directed approach to develop therapeutic PCNA inhibitors.Item Metadata only The structure of a stable serrulatane diterpenoid acetal from eremophila rotundifolia(CSIRO Publishing, 1985) Abell, A.D.; Horn, E.; Jones, G.P.; Snow, M.R.; Massywestropp, R.A.; Riccio, R.The serrulatenol (1a), a stable diterpenoid acetal from remophilia rotundifolia, has been shown to be (13S,18R)-5,18:13,18- diepoxyserrulat-14-en-8-ol by chemical and spectroscopic characterization and by single-crystal X-ray analysis of the p- bromobenzoate . This compound crystallizes as clear prisms in the monoclinic space group P21 with a 9.112(1), b 9.743(2), c 13.423(3) Ǻ, β 102.27(5)° and Z 2. The structural final refinement of a blocked-matrix least-squares calculation converged with R 0.038 and Rw 0.041.Item Metadata only The Synthesis of Peptide-Based Macrocycles by Huisgen Cycloaddition(John Wiley & Sons, 2017) Abell, A.D.; Pehere, A.D.; Marsault, E.; Peterson, M.L.Including case studies of macrocyclic marketed drugs and macrocycles in drug development, this book helps medicinal chemists deal with the synthetic and conceptual challenges of macrocycles in drug discovery efforts.