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Introduction
My research uses a structure-based approach to identify small molecule inhibitors of the KNa1.1 channel using a combination of virtual screening, fluorescence potassium ion channel assays and patch-clamp electrophysiology, with the aim of identifying suitable compounds to develop into therapeutics to treat KCNT1-associated encephalopathies.
Current institution
Additional affiliations
December 2018 - December 2021
Publications
Publications (19)
The P2X7 receptor (P2X7R) plays an important role in diverse conditions associated with tissue damage and inflammation, meaning that the human P2X7R (hP2X7R) is an attractive therapeutic target. The crystal structures of the zebrafish P2X4R in the closed and ATP-bound open states provide an unprecedented opportunity for structure-guided identificat...
The P2X7 receptor is a calcium permeable cationic channel activated by extracellular ATP, playing a role in chronic pain, osteoporosis and arthritis. A number of potential lead compounds are inactive against the rat isoform, despite good activity against the human homologue, making animal model studies problematic. Here we have produced P2X7 models...
P2X receptors are Ca²⁺-permeable cationic channels in the cell membranes, where they play an important role in mediating a diversity of physiological and pathophysiological functions of extracellular ATP. Mammalian cells express seven P2X receptor genes. Single nucleotide polymorphisms (SNPs) are widespread in the P2RX genes encoding the human P2X...
P2X receptors are a group of homo/hetero-trimeric membrane protein complexes with an integral ion channel that opens upon extracellular adenosine triphosphate (ATP) binding (North, 2002; Khakh and North, 2006). There are seven P2X subunits (P2X1-P2X7), all having a membrane topology of cytosolic N- and C-termini, and two transmembrane segments (TM1...
The P2X7 receptor (P2X7R) is important in mediating a range of physiological functions and pathologies associated with tissue damage and inflammation and represents an attractive therapeutic target. However, in terms of their structure-function relationships, the mammalian P2X7Rs remain poorly characterised compared to some of their other P2XR coun...
The P2X7 receptor is an exceptional member of the P2X purinergic receptor family, with its activation requiring high concentrations of extracellular adenosine 5ʹ‐triphosphate (ATP) that are often associated with tissue damage and inflammation. In the central nervous system (CNS), it is highly expressed in glial cells, particularly in microglia. In...
Inflammasomes are assembled by innate immune sensors that cells employ to detect a range of danger signals and respond with pro-inflammatory signalling. Inflammasomes activate inflammatory caspases, which trigger a cascade of molecular events with the potential to compromise cellular integrity and release the IL-1β and IL-18 pro-inflammatory cytoki...
The NLRP3 inflammasome is a vital mediator of innate immune responses. There are numerous NLRP3 mutations that cause NLRP3-associated autoinflammatory diseases (NLRP3-AIDs), mostly in or around the NACHT domain. Here, we present a patient with a rare leucine-rich repeat (LRR) domain mutation, p.Arg920Gln (p.R920Q), associated with an atypical NLRP3...
The P2X7 receptor (P2X7R) is a calcium‐permeable cation channel activated by high concentrations of extracellular ATP. It plays a role in vital physiological processes, particularly in innate immunity, and is dysregulated in pathological conditions such as inflammatory diseases, neurodegenerative diseases, mood disorders, and cancers. Structural mo...
The P2X7 receptor, originally known as the P2Z receptor due to its distinctive functional properties, has a structure characteristic of the ATP-gated ion channel P2X receptor family. The P2X7 receptor is an important mediator of ATP-induced purinergic signalling and is involved the pathogenesis of numerous conditions as well as in the regulation of...
The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalit...
Branched poly( N - iso propylacrylamide) was functionalized with Amphotericin B (AmB) at the chain ends to produce an antifungal material. The polymer showed antifungal properties against AmB-sensitive strains of Candida albicans , Fusarium keratoplasticum and Aspergillus flavus (minimal inhibitory concentration ranged from 5 to 500 µg ml ⁻¹ ) but...
The P2X7 receptor (P2X7R) is an ATP-gated cation channel with a critical role in many physiological and pathological processes, and shows prominent functional differences across mammalian species, exemplified by larger current responses of the rat (r) P2X7R to ATP and its analogue BzATP and a greater sensitivity to agonists compared with the human...
Inflammasomes are key regulators of the host response against microbial pathogens, in addition to limiting aberrant responses to sterile insults, as mediated by environmental agents such as toxins or nanoparticles, and also by endogenous danger signals such as monosodium urate, ATP and amyloid-β. To date at least six different inflammasome signalli...
Autoinflammation as a distinct disease category was first reported in 1999 as a group of monogenic disorders characterized by recurrent episodes of systemic and organ-specific inflammation, known as periodic fever syndromes. Since this original description, the focus has shifted considerably to the inclusion of complex multifactorial conditions wit...
We present here a quantification of the sorption process and molecular conformation involved in the attachment of bacterial cell wall lipopolysaccharides (LPS), extracted from Escherichia coli, to silica (SiO2) and alumina (Al2O3) particles. We propose that interfacial forces govern the physicochemical interactions of bacterial cell wall with miner...
The adverse biological impact of orthopaedic wear debris currently limits the long-term safety of human joint replacement devices. We investigated the role of particle size, surface composition and donor variation in influencing the biological impact of silicon nitride as a bioceramic for orthopaedic applications. Silicon nitride particles were com...
The adamantane scaffold, despite being widely used in medicinal chemistry, is not devoid of problems. In the recent years we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As an adamantane scaffold is a common structural feature in several P2X7 receptor antagonists, herein...