A5052202694- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- Ion Transport and Channel Regulation
- Protein Kinase Regulation and GTPase Signaling
- Carbohydrate Chemistry and Synthesis
- Parkinson's Disease Mechanisms and Treatments
- HIV Research and Treatment
- Autophagy in Disease and Therapy
- Crystallization and Solubility Studies
- DNA and Nucleic Acid Chemistry
- Calcium signaling and nucleotide metabolism
- X-ray Diffraction in Crystallography
- Cancer, Hypoxia, and Metabolism
- Peptidase Inhibition and Analysis
- Cytomegalovirus and herpesvirus research
- Hippo pathway signaling and YAP/TAZ
- 14-3-3 protein interactions
- Cytokine Signaling Pathways and Interactions
- Metabolism, Diabetes, and Cancer
- Signaling Pathways in Disease
- Synthesis and Biological Evaluation
- Ubiquitin and proteasome pathways
- Ferrocene Chemistry and Applications
- Click Chemistry and Applications
- PI3K/AKT/mTOR signaling in cancer
Cardiff University
2016-2025
Discovery Institute
2025
University of Nottingham
2021
University of Birmingham
2014-2017
MRC Protein Phosphorylation and Ubiquitylation Unit
2011-2013
University of Dundee
2010-2013
Arizona State University
2009-2012
BioEnergetics (United States)
2009
The WNK (with no lysine kinase)-SPAK (SPS1-related proline/alanine-rich kinase)/OSR1 (oxidative stress-responsive kinase 1) signalling pathway plays an important role in controlling mammalian blood pressure by modulating the activity of ion co-transporters kidney. Recent studies have identified Gordon's hypertension syndrome patients with mutations either CUL3 (Cullin-3) or BTB protein KLHL3 (Kelch-like 3). assembles proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how...
Mutations in the WNK [with no lysine (K) kinase] family instigate hypertension and pain perception disorders. Of four isoforms, much of focus has been on WNK1, which is activated response to osmotic stress by phosphorylation its T-loop residue (Ser382). isoforms phosphorylate activate related SPAK (SPS1-related proline/alanine-rich kinase) OSR1 (oxidative stress-responsive kinase 1) protein kinases. In present study, we first describe generation double-knockin ES (embryonic stem) cells,...
Niclosamide is an anthelmintic drug that has been used for over 50 years mainly to treat tapeworm infections. However, with the increase in repurposing initiatives, niclosamide emerged as a true hit many screens against various diseases. Indeed, from being drug, it now shown potential treating Parkinson's disease, diabetes, viral and microbial infections, well cancers. Such diverse pharmacological activities are result of niclosamide's ability uncouple mitochondrial phosphorylation modulate...
Since loss of function mutations PINK1 lead to early onset Parkinson's disease, there has been growing interest in the discovery small molecules that amplify kinase activity PINK1. We herein report design, synthesis, serum stability, and hydrolysis four kinetin riboside ProTides. These ProTides, along with riboside, activated cells independent mitochondrial depolarization. This highlights potential modified nucleosides their phosphate prodrugs as treatments for neurodegenerative diseases.
Human Vγ9/Vδ2 T-cells detect tumor cells and microbial infections by recognizing small phosphorylated prenyl metabolites termed phosphoantigens (P–Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P–Ag-mediated activation of T-cells; however, molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P–Ag’s discriminated from nonantigenic molecules. Here, we utilized NMR X-ray crystallography probe P–Ag BTN3A1. Whereas...
Abstract Mutations in PINK1, which impair its catalytic kinase activity, are causal for autosomal recessive early‐onset Parkinson's disease (PD). Various studies have indicated that the activation of PINK1 could be a useful strategy treating neurodegenerative diseases, such as PD. Herein, it is shown anthelmintic drug niclosamide and analogues capable activating cells through reversible impairment mitochondrial membrane potential. With these compounds, first time, demonstrated pathway active...
Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced 1 (PINK1), upon depolarization, is an important intermediate step in recycling of damaged mitochondria via mitophagy. As mutations PINK1 can cause early-onset Parkinson's disease (PD), there has been a growing interest small-molecule activators PINK1-mediated mitophagy as potential PD treatments. Herein, we show that N6-substituted adenosines, such N6-(2-furanylmethyl)adenosine (known kinetin riboside) and...
The protein kinase OSR1 has been highlighted as a biomarker for poor prognosis in breast cancer (BC) patients. To further decipher the mechanism underpinning this, we studied expression, phosphorylation status, and catalytic activity of across series BC cell lines. was found to be expressed various luminal triple negative (TNBC) lines studied, although it only constitutively active highly migratory TNBC line MDA-MB-231. Although this carries p53 mutations, our data indicated that...
SPAK and OSR1 are two protein kinases that have emerged as attractive targets in the discovery of novel antihypertensive agents due to their role regulating electrolyte balance vivo. Herein we report identification an allosteric pocket on highly conserved C-terminal domains these kinases, which influences activity. We also show some known WNK signaling inhibitors bind this site. Using silico screening, identified antiparasitic agent rafoxanide a inhibitor OSR1. Collectively, work will...
Examples of organometallic compounds as nucleoside analogues are rare within the field medicinal bioorganometallic chemistry. We report on synthesis and properties two chiral ferrocene derivatives containing a nucleobase hydroxyalkyl group. These so-called ferronucleosides show promising anticancer activity, with cytostatic studies five different cancer cell lines indicating that both functional groups required for optimal activity.
Abstract The masking of nucleoside phosphate and phosphonate groups by an aryl motif amino acid ester, nowadays known as the ‘ProTide’ technology, has proven to be effective in discovery nucleotide therapeutics. Indeed, this which was invented Chris McGuigan early 1990s, inspired two FDA‐approved antiviral drugs, many more are currently undergoing (pre)clinical development. usefulness technology therapeutics is showcased Highlight discussing ProTides development various that have reached...
A new series of chiral ferrocene derivatives containing both a hydroxyalkyl group and thyminyl on one cyclopentadienyl ring have been synthesised to probe structure–activity relationships in cancer cell line cytotoxicities. The stereoisomers enantiomeric pairs these so‐called ferronucleosides studied characterised by combination analytical HPLC single‐crystal X‐ray diffraction. Biological activity studies revealed that changing the length had marked effects IC 50 values, with compounds...
The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this technology to monophosphate derivative phosphoantigen HMBPP and one its analogues. Some these prodrugs exhibited specific potent activation Vγ9/Vδ2 T-cells, which were then able lyse bladder cancer cells vitro. This work highlights promise discovery novel immunotherapeutics.
STE20/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative-stress-responsive 1 (OSR1) are two serine/threonine protein kinases that play key roles in regulating ion homeostasis. Various SPAK OSR1 mouse models exhibited reduced blood pressure. Herein, the discovery of verteporfin, a photosensitising agent used photodynamic therapy, as potent inhibitor is reported. It shown verteporfin binds domains inhibits their catalytic activity an adenosine triphosphate (ATP)-independent manner....
As part of our studies on the anti-HIV activities 2′,3′-didehydro-2′,3′-dideoxyuridine (d4U), 2′,3′-dideoxyuridine (ddU) and their 'ProTides', we have prepared evaluated activity a range d4U ddU aryl triester phosphoramidates. Besides elucidating SAR characteristics, performed molecular modelling both in order to probe first phosphorylation step required for activation these two nucleoside analogues. Overall, application phosphoramidate approach turned inactive moderately active agent, while...
The MO25 scaffolding protein operates as critical regulator of a number STE20 family kinases (e.g. MST and SPAK isoforms) well pseudokinases STRAD isoforms that play role in activating the LKB1 tumour suppressor). To better understand how interacts stimulates activity kinases, we determined crystal structure MST3 catalytic domain (residues 19-289) complex with full length MO25β. reveals an intricate web interactions between MO25β function to stabilise kinase closed, active, conformation even...
Vγ9/Vδ2 T-cells are activated by pyrophosphate-containing small molecules known as phosphoantigens (PAgs). The presence of the pyrophosphate group in these PAgs has limited their drug-like properties because its instability and polar nature. In this work, we report a novel short Grubbs olefin metathesis-mediated synthesis methylene difluoromethylene monophosphonate derivatives PAg (E)-4-hydroxy-3-methyl-but-2-enyl (HMBP) well aryloxy diester phosphonamidate prodrugs, termed ProPAgens. These...