RESEARCH

 

Lay Research Summary

Our research focuses on understanding the function of proteins that are important in the development and progression of many diseases such as Parkinson’s disease, hypertension and cancer. We utilise the improved understanding of these diseases to discover new drugs that treat them. To successfully achieve our research goals, we employ techniques and skills from different scientific fields including chemistry, biology and medicine. Through this research discovery process, we aim to inspire students and offer them outstanding training opportunities to become successful scientists and researchers.

Collectively, our research and training opportunities will have far reaching impact that covers science, education, health, the economy, quality of life and general well-being. 

Summary of Research Projects

1. Parkinson’s Disease: PINK1/Parkin signalling

Mutations in PINK1, a mitochondrial protein kinase, and Parkin, an E3 ubiquitin ligase, are causative of early-onset Parkinson's disease. Several studies have indicated that the activation of PINK1 abrogates neuronal apoptosis. Thus, the activation of PINK1 emerged as a promising strategy for treating neurodegenerative diseases such as Parkinson's disease. 

Our lab has been working on the discovery of small molecule PINK1 activators as potential treatments for Parkinson’s disease. To this end, we discovered the clinically used agent niclosamide as a potent activator of PINK1 in cells and neurons. The mechanism by which niclosamide activates PINK1 does not seem to be direct and rather involves reversible depolarisation of the mitochondrial membrane. Beyond niclosamide, we also discovered kinetin riboside also activates PINK1 in cells more potently than the nucleobase kinetin, which had been previously reported as a PINK1 activator. Additionally, we also showed that the monophosphate prodrugs of kinetin riboside, namely ProTides, exhibited potent activation of PINK1 in cells. Current efforts are focusing on optimising these hit compounds into brain-penetrant, potent PINK1 activators that could potentially treat Parkinson’s disease.

2. Cancer and Infections: T-cell immunotherapy

Activating the immune system to eradicate cancer and viruses is a promising alternative approach to treat these diseases. For our lab, the focus has been on a subset of T-cells known as the Vγ9/Vδ2 T-cells. These are a small subset of T-cells that are present since birth and expand significantly in the presence of infections and cancer. Vγ9/Vδ2 T-cells are activated by small molecule phosphoantigens such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). Considering the structure of HMBPP, we hypothesised that the pyrophosphate group would limit its use as a drug in humans to treat cancer and infections. Hence, we embarked on making prodrugs of the monophosphate derivative of HMBPP, namely (E)-4-hydroxy-3-methylbut-2-enyl phosphate (HMBP). We first reported the application of the aryloxy triester phosphoramidate prodrug approach to HMBP. We termed this prodrug approach as the ProPAgen approach; prodrugs of phosphoantigens Although these showed some potent activation of Vγ9/Vδ2 T-cells, their stability was poor. We subsequently applied the prodrug approach to the more stable phosphonates of HMBP. These exhibited sub-nanomolar potency in activating the Vγ9/Vδ2 T-cells coupled with excellent stability profiles in human serum. Currently, we are exploring the therapeutic potential of these prodrugs to treat various diseases. 

3. Mitochondrial Diseases: nucleoside and nucleotide therapy

Mutations in the genes that encode mitochondrial deoxynucleoside kinases lead to impairment in mitochondrial DNA (mDNA) synthesis, which can be manifested in devastating muscular and neurological diseases. Although to date no effective treatment for these diseases exists, there have been recent reports indicating the use nucleosides and nucleotides to treat these mDNA-depletion diseases. Given our long-standing track-record in nucleosides/nucleotides chemistry and drug discovery, we became fascinated by such discovery and have since been applying our know how in designing modified nucleoside and nucleotides that have the potential to treat mDNA depletion diseases. Our focus has been on improving the drug-like properties of nucleosides and nucleotides so they could be more effective in treating diseases in humans. 

4. Cancer and Autoimmune Diseases: SH2 domain inhibitors

The binding of phosphotyrosine to the Src Homology 2 (SH2) domain of many proteins is a critical step in the signal transduction of many diseases including cancer and autoimmune diseases. The inhibition of such binding has been validated in vivo as a promising approach to treat these diseases. However, the specific targeting of these SH2 domains by small molecules has proved a stern challenge. To address this challenge, we have been using new phosphate bioisosteres to discover specific SH2 domain inhibitors. Our focus has so far been on the specific targeting of the STAT3 SH2 to discover new medicines for breast and colorectal cancers. Recently, we reported the application of the aryloxy triester phosphoramidate prodrug technology to a phosphotyrosine-containing STAT3 inhibitor as means of improving its cellular uptake and thus its efficacy. This work provided a solid proof of concept for the use of this technology to improve the drug-like properties of phosphotyrosine-containing compounds. More on this will be shared soon. 

5. Hypertension: WNK-SPAK/OSR1 signalling

SPAK and OSR1 are two protein kinases that become activated under osmotic stress by WNK kinases, whose mutation in humans cause hypertension. Various SPAK and OSR1 knock-in in vivo models exhibited reduced blood pressure indicating the inhibition of SPAK and OSR1 kinases as a promising strategy in lowering blood pressure. Encouraged by this, our lab has focused on the discovery of small molecules that could inhibit SPAK and OSR1 kinases and which could be developed as new drugs to treat hypertension. Initially, we discovered a small molecule, known as HK01, as an inhibitor of the binding of SPAK and OSR1 kinases to a protein activator called MO25. This was a proof-of-concept that targeting MO25 with small molecules to inhibit its activation of SPAK and OSR1 kinases was feasible. We also discovered that the binding of SPAK and OSR1 kinases is enhanced by the phosphorylation of a highly conserved serine residue on their C-terminal domains. Subsequently, we showed that a small pocket in the C-terminal domains of SPAK and OSR1 kinases, known as the secondary pocket, could influence their kinase activity. In fact, we showed that some reported SPAK and OSR1 kinase inhibitors may bind this site. Using high throughput screening, we identified Verteporfin, an FDA-approved agent as a potent inhibitor of SPAK and OSR1 kinases though it was not very specific. We are currently working on optimising the structures of these hit SPAK and OSR1 inhibitors with the view of improving their potency and selectivity and hopefully developing them as novel antihypertensive agents.

Other than discovering new drugs that target SPAK and OSR1 kinases, we are also working on understanding how SPAK and OSR1 kinases are regulated in cells and what else they do beyond phosphorylating ion co-transporters.

 

Collaborators:

Our projects cross many disciplines and are highly collaborative. We are grateful to the valuable contributions and input of all of our collaborators. 

Work in the lab has been funded by:

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School of Pharmacy and Pharmaceutical Sciences

Redwood Building, King Edward VII Avenue

Cardiff University, Cardiff CF10 3NB, UK