Peptide thioamides, in which a single backbone oxygen atom is replaced by sulfur, display markedly altered structural, spectroscopic and reactive properties relative to native amides. This personal perspective highlights our group’s exploration of the unique reactivity of peptide thioamides and the development of AgI-promoted transformations that exploit this subtle but powerful single-atom substitution. Initial studies demonstrated that thioamides undergo silver-mediated coupling with carboxylates to generate reactive isoimide intermediates that can then undergo 1,3-acyl transfer to generate imides, or be intercepted by appropriately reactive and positioned nucleophiles. This mechanistic platform has enabled the development of a diverse range of peptide transformations, including a N→C direction approach to peptide synthesis, an Asn-based ligation strategy, amino acid insertion and ring expansion of cyclic peptide thioamides, intermolecular peptide fragment couplings and a rapid, traceless, epimerisation-free method for head-to-tail peptide macrocyclisation. Extension of this chemistry to side-chain nucleophiles enabled late-stage macrolactonisation approaches to depsipeptides, together with backbone thioamide-directed Asp activation for peptide stapling and site-selective N-glycosylation. More recent work has explored peptide thioamides as versatile precursors to additional backbone isosteres and directing groups, including amidoxime ethers for late-stage C–H functionalisation. Collectively, these studies demonstrate how a seemingly minor O→S substitution can profoundly alter peptide reactivity, enabling chemoselective transformations and synthetic strategies that are difficult to achieve using native amide chemistry.
Hydrogels are excellent biomaterials widely used in medicine, industry and agriculture. Self-healing hydrogels have garnered significant interest, yet they typically exhibit poor mechanical strength. Research shows that the mechanical strength of hydrogels can be significantly enhanced by introducing a second-layer network structure. Based on this, a simple solution blending method was adopted in this study. Hydroxyethyl cellulose (HEC), serving as both a reinforcing component and a second network, was introduced into the dynamic cross-linking system composed of the main raw materials, polyvinyl alcohol (PVA) and borax, and a double-network hydrogel was successfully fabricated. The tensile and compressive strengths of the hydrogel with 1 wt% HEC reached 4.77 ± 0.29 and 4.94 ± 0.34 kPa, which were 4.04 and 2.77 times those of the pure hydrogel respectively. The hydrogel could achieve fracture healing after being left standing at room temperature for 30 s and its self-healing behaviour was supported by dynamic rheological cyclic tests. Quantitative tests revealed that the hydrogel achieved a self-healing efficiency η of 88.7% after healing at room temperature for 1 h. This research provides a practical and effective approach for constructing high-strength self-healing hydrogels based on cellulose reinforcement design, which is expected to lay a foundation for the expansion of the practical application of such materials.
Tri-butyl phosphate (TBP) is an organic chelate that was used in the 1960s at the Lucas Heights Laboratories of the Australian Atomic Energy Commission (AAEC) before being disposed in sealed containers in trenches at a nearby waste site across a discrete 8-year period. The first study investigating whether TBP was still present at the site was conducted in 2016, which detected low levels of TBP. The aim of the current study was to assess whether the TBP concentrations had changed and, if so, what environmental factors could have contributed to this outcome. This was achieved using a multidisciplinary and two-ways knowing approach, which combines Indigenous knowledge with multiple modern analytical assessments. In 2023, solid-phase extraction (SPE) of groundwater samples was combined with ultra high-pressure liquid chromatography–time of flight–mass spectrometry (UHPLC-TOF-MS) analysis. The results indicate the TBP present at the site is contained within the main trenched area; all other areas were at or below detection limits. These results are significantly lower than those obtained 7 years earlier using gas chromatography–mass spectrometry (GCMS). However, as the GCMS instrument used previously was less sensitive, these same samples were reanalysed using UHPLC-TOF-MS. Comparing the results from these two instruments provided similar trends. In brief, a small amount of TBP appears to remain stable whether it was stored within the original source containers or released to the waste trenches. The only uncontrolled variable entering or leaving the trenched area was water. Results from two extreme rain events from 2016 show that TBP concentrations fluctuate with the rise and fall of the groundwater, indicating a link between water and TBP’s mobilisation. This illustrates that the original disposal of TBP in sealed containers, if they remain completely separated from the environment, is a disposal method. It seems likely that failure in one or more containers is the point source of TBP. The selected site had the attributes of a stable geology and impermeable clay, which help to contain the contaminants long term. To some extent, this is consistent with Care for Country principles. No further wastes have been added to the main trenched area since 1968 and no further waste will be added. Therefore, TBP should diminish over time due to exposure to natural environmental processes, thus allowing Country to heal.
Mahinga kai (food gathering) activities are culturally important and still practised in the Te Arawa Rotorua Lakes, Aotearoa–New Zealand. Owing to active geothermal inputs in this region, heavy metal concentrations can be high and knowledge of their distributions is critical for undertaking mahinga kai practices. Whether it is safe to harvest kai (food) from Lake Tarawera, and whether risk varies spatially within the lake, were explored, guided by and centred on the priorities of the iwi (tribe) Tūhourangi. The concentrations of As, Cd, Cu, Fe, Pb, Mn, Hg and Zn in kākahi, Echyridella menziesii (Gray, 1843), and water, were analysed from five wadable locations around the lake. Heavy metal concentrations in kākahi tissues and the lake water varied among locations, but rank orders for each did not vary similarly. Kākahi near the lake outlet had the highest concentrations of all heavy metals except Pb, which was highest near a residential area. In the water samples, the highest concentrations of each heavy metal varied among sites. Water movement near the outlet likely increased mussel clearance rates and the transfer of heavy metals and organic matter towards this site, leading to higher concentrations in kākahi there. A potential significant risk may arise when consuming kākahi or lake water from Lake Tarawera. However, spatial variation in heavy metals means that representing the whole lake with a single risk value for consumption may not accurately reflect the variability of risk. Tūhourangi can use this study to inform mahinga kai practices within Lake Tarawera.
Background Indigenous Knowledge (IK) and Traditional Knowledge (TK) have long contributed to global health through the sustainable use of medicinal plants. Yet, their integration into pharmaceutical research and development (R&D) often occurs without adequate recognition, protection or benefit sharing for the knowledge holders. This paper explores how IK and TK are used in early-stage drug discovery and reflects on the ethical, scientific and regulatory implications of their application. Methods We developed two hypothetical case vignettes to illustrate common research scenarios involving the use of IK and TK: one based on non-codified, orally transmitted knowledge shared directly by an Indigenous community; and the other based on codified historical medicinal knowledge sourced from historical botanical texts, where provenance may be unclear or obscured. These vignettes were developed using Both-Ways Collaborative Yarning and reflexive thematic analysis, informed by existing literature and expert validation. Results The vignettes highlight the strengths and limitations of current research models, particularly regarding knowledge provenance, methodological validity, community participation and benefit sharing. The non-codified case demonstrated the importance of community-led processes and contextualised preparation methods, whereas the codified case raised questions around the ethical use of archived knowledge with uncertain origins, including issues of provenance, accountability and potential misappropriation. Both cases demonstrated the efficiency and value of IK and TK in narrowing down viable drug candidates compared to conventional random screening methods. Conclusion The findings underscore the need for more inclusive and culturally safe R&D frameworks that centre Indigenous sovereignty, implement free, prior and informed consent (FPIC), integrate holistic approaches to knowledge and include culturally aligned R&D methods. By adopting a two-ways knowing approach, researchers and institutions can more ethically and effectively partner with Indigenous people and communities to advance drug discovery while respecting the integrity of their knowledge systems.
Naturally derived products, including plant- and venom-derived peptides, have played an instrumental role in identifying the ion channels, receptors and signalling pathways involved in visceral pain. Although crude venoms are traditionally known for their harmful effects, research into their molecular composition has uncovered a diverse array of peptide components with high specificity for particular ion channels and receptors. These peptide components exhibit potent excitatory and inhibitory properties, including the ability to alter neuronal excitability. This review highlights key naturally derived products and peptides that have been invaluable tools in advancing our understanding of both pro-nociceptive and anti-nociceptive mechanisms in visceral pain. Beyond their value as molecular tools, these compounds represent promising scaffolds for the development of novel therapeutics, with the potential to significantly transform the clinical management of visceral pain.
In this article, using NNIP (2-(2-nitronaphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) as a ligand to synthesise and characterise a new iridium(III) complex, [Ir(piq)(2)(NNIP)]PF6 (Ir1, where piq = 1-phenylisoquinoline) and to explore its anticancer activity as a photosensitiser against HeLa cancer cells and the corresponding mechanisms of inducing cancer cell death. The cytotoxicity of Ir1 against HeLa, B16 and normal NIH3T3 cells was assessed using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Unexpectedly, Ir1 initially shows no cytotoxicity against those cells (half maximal inhibitory concentration, IC50 > 200 mu M) in the dark. However, upon white light irradiation, Ir1 significantly increased cytotoxicity, especially on HeLa cancer cells with a low IC50 value of 3.1 +/- 0.3 mu M. The anticancer mechanism was explored through various techniques, including cellular uptake, mitochondrial co-localisation, ROS production, mitochondrial permeability transition pore opening and the change in the mitochondrial membrane potential. Subsequently, lipid peroxidation was investigated with a C11-BODIPY581/591 probe to affirm the occurrence of ferroptosis. Additionally, metabolic impacts were probed by conducting lactate dehydrogenase release and adenosine 5 '-triphosphate (ATP) quantification assays. Apoptosis, pyroptosis and immunogenic cell death were also explored. The light-activated antitumour in vivo revealed that Ir1 can effectively inhibit the tumour growth with an inhibitory rate of 53.2%. These findings demonstrate that Ir1 induces cancer cell demise by a mitochondrial apoptotic pathway mediated by ROS, ferroptosis and pyroptosis.
Size modulation and nitrogen doping are considered potential strategies for tuning the optical and electronic properties of biphenylene quantum dots (BPQDs), yet the underlying synergistic mechanisms between these two factors remain unclear. In this work, density functional theory (DFT) and time-dependent DFT (TDDFT) were employed to systematically investigate the combined effects of nine sizes, three nitrogen doping types (edge, surface and pyridinic) and three doping concentrations (2N, 4N, 6N) on the structural, optical and electronic behaviour of BPQDs. The results reveal distinct dependencies of optical and electronic modulation on dopant type and quantum dot size. Edge and surface nitrogen doping consistently lead to red-shifted absorption and band-gap narrowing across all sizes and concentrations, with modulation strength strongly dependent on both size and doping concentration. A blue shift appears exclusively in the large-sized, high-concentration surface-doped system (surf-6N-C96). By contrast, pyridinic doping exhibits a uniformly weak effect, leading to slight red shifts and band-gap reductions that are essentially independent of both size and concentration. These findings highlight the type-specific and size-dependent nature of doping in BPQDs and provide mechanistic insights into the synergistic regulation of their optoelectronic properties, offering theoretical guidance for the rational design of carbon-based quantum materials.
A distinctive continuous-flow synthesis of 2,2,2-trifluoro-1-(3 '-methoxy-[1,1 '-biphenyl]-4-yl)ethan-1-ol, an important intermediate for the synthesis of a tryptophan hydroxylase inhibitor LX1031, is described. The pivotal synthetic process involved a photochemically induced nickel-catalysed radical cross coupling of phthalimido trifluoroethanol with 1-bromo-4-(3-methoxyphenyl)benzene. This approach not only enhanced synthetic efficiency but also demonstrated the potential of flow photochemistry for the synthesis of a complicated pharmaceutical intermediate on a gram scale.
Natriuretic peptides (NPs) are body fluid volume modulators that have implications in the treatment and management of several conditions, including heart failure, chronic respiratory disease and renal dysfunction. Congestive heart failure is a major burden for the health system; thus, improved therapeutics for the treatment of this condition are highly desired. The natriuretic and diuretic properties of the natriuretic peptides make them ideal candidates for the treatment of congestive heart failure. However, current therapeutics from this family of peptides are far from ideal and suffer from poor pharmacokinetic properties. In the last 20 years, there has been growing interest in NPs from reptilian venom due to high potency and stability. In the present work, Tadendocor (TDT), a chimeric NP, has been produced, which is a combination of the N- and C-terminal tails of taipan natriuretic peptide c (TNPc) from Oxyuranus microlepidotus with the 17-residue intramolecular ring of Dendroaspis natriuretic peptide (DNP) from Dendroaspis angusticeps. This peptide was found to possess increased stability to a range of endopeptidases and proteases and was active at human natriuretic peptide receptor A (hNPR-A) with similar potency to human atrial natriuretic peptide (hANP). Point mutations within the intramolecular ring further increased the potency at hNPR-A, with the H12R, N22G mutant being the most active. Mini-PEGylation with a variety of branched and linear PEG groups did not significantly affect the potency of Nle 29 TDT [H12R/N22G] at hNPR-A, but allowed for oral delivery in vivo. The attachment of a >20-kDa PEG group reduced the potency at hNPR-A by 10-fold but significantly increased the half-life in vivo. This chimeric snake NP represents a promising candidate for the development of a stable, potent NP therapeutic for heart failure.
The adsorption of glyphosate on pristine and monodoped graphene was investigated using Density Functional Theory at the PBE-D3/def2-SVP level together with molecular dynamics simulations. Graphene sheets doped with Fe3+, Fe2+, Al3+, Cu2+, Zn2+, Mn2+, Ca2+ and Mg2+ were modeled by substituting a carbon atom in a finite graphene cluster, followed by full geometry optimization in the gas phase. Thermodynamic parameters, including adsorption energy, enthalpy, Gibbs free energy and equilibrium constants, were obtained from vibrational frequency analyses. Fe3+- and Al3+-doped systems exhibited the most favorable interactions, with Gibbs free energy values of -18.69 and -18.88 eV respectively, indicating spontaneous and strong adsorption. Quantum Theory of Atoms in Molecules and Non-Covalent Interaction analyses revealed mixed adsorption character, with contributions from physisorption and localized chemisorption regions in Fe3+ and Al3+ complexes. Molecular dynamics simulations at 298 K over 8 ns showed that doped systems maintained higher structural stability than pristine graphene, as confirmed by root mean square deviation analyses. All simulations were performed in a vacuum to assess intrinsic adsorption properties. This integrated computational approach demonstrates that Fe3+ and Al3+ doping significantly enhances glyphosate binding through cooperative non-covalent and coordinative interactions, highlighting the potential of metal-doped graphene as a rationally designed adsorbent for environmental remediation.
The insertion of a silicone intestinal obstruction catheter is a common and effective approach for managing an acute surgical abdomen. However, patients often experience significant nasopharyngeal discomfort and pain during both catheter placement and prolonged indwelling. To reduce insertion difficulty, patient discomfort and the risk of microbial infection, we developed a straightforward fabrication method to produce an epoxy-polydimethylsiloxane (EP/PDMS)-nSiO2 coating. Experimental results demonstrate that the unique microstructure of the coating confers excellent hydrophobic and lubricating properties. Notably, the coating retained its hydrophobicity and lubricity even after 60 days of immersion in acidic and alkaline solutions. Furthermore, the coating exhibited antibacterial adhesion properties and cytotoxicity assessments confirmed that it caused no significant damage or toxicity to L929 cells.
Two novel indole-based porous organic polymers, InPhHCP-7 and InMelPOP, were synthesised using Friedel-Crafts alkylation and acetal reactions respectively. InPhHCP-7 was specifically designed for CO2 adsorption, whereas InMelPOP was developed for the removal of iodine species from aqueous solution. Under a pure dry CO2 atmosphere, the CO2 adsorption capacity of InPhHCP-7 reached 2.28 mmol g-1 at 25 degrees C and 100 kPa, with negligible performance degradation over three adsorption-desorption cycles. The adsorption mechanism is predominantly physical in nature. For InMelPOP, 1.978 g g-1 of I2 adsorption capacity was achieved when 50.0 mg of the material was soaked in 3 mL of 1 & times; 105 mg L-1 KI3 aqueous solution for 48 h. The I2 adsorption capacity could still retain 1.620 g g-1 after three cycles. The iodine adsorption process involves both physical and chemical interactions. Both materials exhibit superior adsorption performance compared to most previously reported porous organic polymers. Their adsorption performance is governed by the synergistic interplay between hierarchical pore architecture and the presence of multiple active adsorption sites. This study provides both experimental evidence and theoretical insights for the efficient capture of CO2 and iodine species.
Cyclic peptides are increasingly recognised as a therapeutic modality for modulating intracellular protein-protein interactions (PPIs), including those considered 'undruggable' by small molecules or biologics. Cyclic gomesin (cGm), an 18-residue beta-hairpin peptide containing two disulfide bonds and a cyclised backbone, combines high chemical stability with amphipathic character that promotes selective interaction with negatively charged cancer cell membranes. We previously showed that cGm enters cancer cells at non-toxic concentrations by endocytosis and direct membrane partitioning, outperforming established cell-penetrating peptides, and that it can be engineered to incorporate a sequence that inhibits PPIs involved in lactate dehydrogenase-5 tetramerisation. Here, we further assess its grafting capacity by incorporating bioactive loop sequences of varying size, charge and hydrophobicity into the cGm framework. Structural and biophysical analyses confirmed that grafted analogues retained the three-dimensional fold and had membrane-binding features, anticancer activity, melanoma selectivity and low toxicity toward non-cancerous cells. These findings demonstrate the tolerance of cGm to sequence variation and support its development as a modular scaffold for designing intracellularly active cyclic peptide therapeutics.
Conotoxin chi-Mr1a, a 13 residue conotoxin that has two disulfide bonds in the ribbon fold, is found in the venom of the predatory marine snail, C. marmoreus. It noncompetitively inhibits the human norepinephrine transporter (hNET), leading to reduced allodynia in animal models of neuropathic pain. Rational design was used to prune conotoxin chi-Mr1a while maintaining the pharmacophore that led to the development of an equipotent mimetic (half maximal inhibitory concentration, IC50: 760 nM). Surprisingly, oxidative folding of the reduced linear peptide led to four rather than the expected three isoforms. Detailed investigation led to the discovery of two stereotopological isoforms, one of which in the globular fold was >1000 fold more potent than the other isoform, both in vitro and in vivo in an allodynia mouse model. Stereotopological isoforms have never been reported for conotoxins and represent an additional level of structural complexity with implications for rational design, chemical synthesis and structural diversity of cysteine rich peptides.
We introduce a flexible reactor platform for testing electrocatalysts, especially for gas-phase reactants or products. This open-source, 3D-printable platform has been designed for gaseous reagents in general and is readily modified to suit a range of applications, configurations and reactor sizes. We demonstrate the versatility of our platform with iridium(IV) oxide as a standard catalyst for water splitting, using a range of conditions that relate the system's performance to the literature. To encourage adoption of our system, we have included detailed build instructions, 3D-printing tips, example reactor configurations and a guide on modifying the provided design code. It is our hope that the simplicity, low-cost and provision of design files will encourage use of the system to more easily enable appropriate testing of gas-diffusion electrocatalysts that will allow for ready cross-laboratory comparison and benchmarking.
As part of our commitment to empowering Indigenous youth and promoting broader appreciation of Australian Indigenous peoples' knowledges, we have developed science activities centred on antioxidant testing of customarily used plants. Conventional antioxidant assays, such as those based on 2,2 '-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power and total phenolic content, often require reagents that are hazardous, costly or difficult to obtain. By contrast, the assay developed here employs safe, low-cost and readily available materials, while providing results comparable to established methods. Based on the redox properties of Betadine (a povidone-iodine complex) and the intense blue colour formed in a starch-Betadine solution, this Blue Betadine Antioxidant Test (BBAT) demonstrated quantitative agreement with the assays listed above for a range of antioxidant compounds (e.g. r2 = 0.989 based on catechin). When applied to extracts from 10 customarily used Australian native plants, the BBAT results were in good agreement with conventional assays, with results most closely aligned with ABTS and DPPH (concordance correlation coefficients >= 0.95). The BBAT is a safe and accessible method suitable for research, education and outreach, providing a culturally relevant platform for exploring the antioxidant properties of customarily used medicinal and food plants.
We report the synthesis and characterisation of stable RhI and IrI half-sandwich complexes supported by redox-active zwitterionic cyclopentadienyl (ZCp) ligands. Using imidazolium-substituted ZCp (IZCp), we isolated well-defined complexes, [ZCpM(COD)]BF4 (M = Rh, Ir) and confirmed their structures by single-crystal X-ray diffraction. Electrochemical studies revealed a reversible one-electron reduction for the Ir complex and DFT analysis demonstrated substantial spin delocalisation on the IZCp ligand, evidencing its non-innocent redox character. Beyond fundamental redox chemistry, we evaluated the Ir complex for parahydrogen-based nuclear spin hyperpolarisation. Parahydrogen-induced polarisation (PHIP) through catalytic hydrogenation of styrene was demonstrated, showing that ZCp-Ir complexes can serve as functional platforms for parahydrogen-based hyperpolarisation. These findings establish zwitterionic Cp ligands as a new platform for stabilising low-valent group 9 metallocenes and for tuning their redox-responsive electronic structures.
The sialic acid family of cell surface carbohydrates is important for maintaining healthy cellular communication and plays a role in cancer and infectious diseases. Monitoring of cell sialylation and free sialic acids can serve as important biomarkers for several diseases. The glycerol tail of the common sialic acid N-acetylneuraminic acid has an affinity for boronic acids and this interaction has been used to detect this sugar fluorescently. This review covers the development of small molecule fluorophores to signal sialic acid binding by boronates and the application of such molecules for the detection of cell surface sialylation. In addition, boronic acids have frequently been incorporated into gold nanoparticles to detect both free and cell-surface sialic acids through multivalent interactions.
This foreword summarises papers submitted by 2024–2025 winners of RACI and AAS awards. This article belongs to the collection: 2024–25 RACI and AAS Award papers.
