Dr Youcef Mehellou

Reader

: Available for postgraduate supervision

School of Pharmacy and Pharmaceutical Sciences

I joined Cardiff School of Pharmacy and Pharmaceutical Sciences in January 2017 where I am now a Senior Lecturer in Medicinal Chemistry. Prior to this, I held a Lectureship position at the University of Birmingham.

After receiving my MPharm degree from King’s College London in 2005, I joined the lab of Prof. Chris McGuigan at Cardiff University for a PhD in Medicinal Chemistry. In early 2009, I moved to Arizona State University (USA) to work as a postdoctoral scientist with Prof. Sidney M. Hecht on the synthesis of unnatural amino acids. In mid-2010, I was awarded an MRC Career Development Fellowship that was held in the lab of Prof. Dario R. Alessi FRS, University of Dundee, until March 2013 when I joined the University of Birmingham.

Current active projects in the lab are:

Parkinson’s Disease: PINK1/Parkin signalling.
Cancer and Infections: T-cell immunotherapy.
Mitochondrial Diseases: nucleoside and nucleotide therapy.
Cancer and Autoimmune Diseases: SH2 domain inhibitors.
Hypertension: WNK-SPAK/OSR1 signalling.

Further details on these projects could be found on www.mehelloulab.com/research

Qualifications

MPharm (Pharmacy), King’s College London, 2005.
PhD in Medicinal Chemistry. Cardiff University, 2009.

Date
Type

2022

Elvers, K. T., Lipka-Lloyd, M., Trueman, R. C., Bax, B. D. and Mehellou, Y. 2022. Structures of the human SPAK and OSR1 conserved C-terminal (CCT) domains. ChemBioChem 23(1), article number: e202100441. (10.1002/cbic.202100441)

2021

Alanazi, A. S., Miccoli, A. and Mehellou, Y. 2021. Aryloxy pivaloyloxymethyl prodrugs as nucleoside monophosphate prodrugs. Journal of Medicinal Chemistry 64(22), pp. 16703–16710. (10.1021/acs.jmedchem.1c01490)
Xu, Q., Taher, T. E., Ashby, E., Sharif, M., Willcox, B. E. and Mehellou, Y. 2021. Generation of stable isopentenyl monophosphate aryloxy triester phosphoramidates as activators of Vγ9Vδ2 T cells. ChemMedChem 16(15), pp. 2375-2380. (10.1002/cmdc.202100198)

2020

Elzwawi, A., Grafton, G., Barnes, N. M. and Mehellou, Y. 2020. SPAK and OSR1 kinases bind and phosphorylate the β2-Adrenergic receptor. Biochemical and Biophysical Research Communications 532(1), pp. 88-93. (10.1016/j.bbrc.2020.07.143)
Kadri, H. et al. 2020. Aryloxy diester phosphonamidate prodrugs of phosphoantigens (ProPAgens) as potent activators of Vγ9/Vδ2 T-Cell immune responses. Journal of Medicinal Chemistry 63(19), pp. 11258-11270. (10.1021/acs.jmedchem.0c01232)
Miccoli, A., Dhiani, B. A., Thornton, P. J., Lambourne, O. A., James, E., Kadri, H. and Mehellou, Y. 2020. Aryloxy triester phosphoramidates as phosphoserine prodrugs: a proof of concept study. ChemMedChem 15(8), pp. 671-674. (10.1002/cmdc.202000034)
Dhiani, B. A. and Mehellou, Y. 2020. The Cul4‐DDB1‐WDR3/WDR6 complex binds SPAK and OSR1 kinases in a phosphorylation‐dependent manner. ChemBioChem 21(5), pp. 638-643. (10.1002/cbic.201900454)

2019

AlAmri, M. A., Jeeves, M. and Mehellou, Y. 2019. Sequence specific assignment and determination of OSR1 C-terminal domain structure by NMR. Biochemical and Biophysical Research Communications 512(2), pp. 338-343. (10.1016/j.bbrc.2019.03.065)
Miccoli, A., Dhiani, B. and Mehellou, Y. 2019. Phosphotyrosine prodrugs: design, synthesis and anti-STAT3 activity of ISS-610 aryloxy triester phosphoramidate prodrugs. MedChemComm 10(2), pp. 200-208. (10.1039/C8MD00244D)
Alanazi, A. S., James, E. and Mehellou, Y. 2019. The protide prodrug technology: Where next?. ACS Medicinal Chemistry Letters 10(1), pp. 2-5. (10.1021/acsmedchemlett.8b00586)

2018

Lambourne, O. A. and Mehellou, Y. 2018. Chemical strategies for activating PINK1, a protein kinase mutated in Parkinson's Disease. ChemBioChem 19(23), pp. 2433-2437. (10.1002/cbic.201800497)
AlAmri, M. A., Kadri, H., Jeeves, M., Alderwick, L. J. and Mehellou, Y. 2018. The photosensitizing clinical agent verteporfin is an inhibitor of SPAK and OSR1 kinases. ChemBioChem 19(19), pp. 2072-2080. (10.1002/cbic.201800272)
Mehellou, Y., Alamri, M. A., Dhiani, B. A. and Kadri, H. 2018. C -terminal phosphorylation of SPAK and OSR1 kinases promotes their binding and activation by the scaffolding protein MO25. Biochemical and Biophysical Research Communications 503(3), pp. 1868-1873. (10.1016/j.bbrc.2018.07.128)
Kadri, H., Lambourne, O. A. and Mehellou, Y. 2018. Niclosamide, a drug with many (re)purposes. ChemMedChem 13(11), pp. 1088-1091. (10.1002/cmdc.201800100)
Mehellou, Y., Rattan, H. S. and Balzarini, J. 2018. The ProTide prodrug technology: from the concept to the clinic. Journal of Medicinal Chemistry 61(6), pp. 2211-2226. (10.1021/acs.jmedchem.7b00734)
Davey, M. S. et al. 2018. Synthesis and biological evaluation of (E)-4-hydroxy-3-methylbut2-enyl phosphate (HMBP) aryloxy triester phosphoramidate Prdrugs as activators of Vγ9/Vδ2 T-cells immune response. Journal of Medicinal Chemistry 61(5), pp. 2111-2117. (10.1021/acs.jmedchem.7b01824)
Barini, E. et al. 2018. The anthelmintic drug niclosamide and its analogues activate the Parkinson's Disease associated protein kinase PINK1. Chembiochem 19(5), pp. 425-429. (10.1002/cbic.201700500)

2017

Salim, M. et al. 2017. BTN3A1 discriminates γδ T cell phosphoantigens from non-antigenic small molecules via a conformational sensor in its B30.2 domain. ACS Chemical Biology 12(10), pp. 2631-2643. (10.1021/acschembio.7b00694)
AlAmri, M. A., Kadri, H., Dhiani, B. A., Mahmood, S., Elzwawi, A. and Mehellou, Y. 2017. WNK-signaling inhibitors as potential new antihypertensive drugs. Chemmedchem (10.1002/cmdc.201700425)
Alamri, M. A., Kadri, H., Alderwick, L. J., Simpkins, N. S. and Mehellou, Y. 2017. Rafoxanide and Closantel inhibit SPAK and OSR1 kinases by binding to a highly conserved allosteric site on their C-terminal domains. ChemMedChem 12(9), pp. 639-645. (10.1002/cmdc.201700077)
Osgerby, L. et al. 2017. Kinetin riboside and its ProTides activate the Parkinson's Disease associated PTEN-Induced Putative Kinase 1 (PINK1) independent of mitochondrial depolarization. Journal of Medicinal Chemistry 60(8), pp. 3518-3524. (10.1021/acs.jmedchem.6b01897)
Kadri, H., Alamri, M. A., Navratilova, I. H., Alderwick, L. J., Simpkins, N. S. and Mehellou, Y. 2017. Towards the development of small molecule MO25-binders as potential indirect SPAK/OSR1 kinase inhibitors. ChemBioChem 18(5), pp. 460-465. (10.1002/cbic.201600620)
Kedge, J. L. et al. 2017. Organometallic nucleoside analogues: effect of hydroxyalkyl linker length on cancer cell line toxicity. European Journal of Inorganic Chemistry 2017(2), pp. 466-476. (10.1002/ejic.201600853)

2016

Thornton, P. J., Kadri, H., Miccoli, A. and Mehellou, Y. 2016. Nucleoside phosphate and phosphonate prodrug clinical candidates. Journal of Medicinal Chemistry 59(23), pp. 10400-10410. (10.1021/acs.jmedchem.6b00523)
Mehellou, Y. 2016. The ProTides boom. Chemmedchem 11(11), pp. 1114-1116. (10.1002/cmdc.201600156)

2014

Nguyen, H. V. et al. 2014. Organometallic nucleoside analogues with ferrocenyl linker groups: Synthesis and cancer cell line studies. Journal of Medicinal Chemistry 57(13), pp. 5817-5822. (10.1021/jm500246h)

2013

Ohta, A. et al. 2013. The CUL3–KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochemical Journal 451(1), pp. 111-122. (10.1042/BJ20121903)
Mehellou, Y., Alessi, D. R., Macartney, T. J., Szklarz, M., Knapp, S. and Elkins, J. M. 2013. Structural insights into the activation of MST3 by MO25. Biochemical and Biophysical Research Communications 431(3), pp. 604-609. (10.1016/j.bbrc.2012.12.113)

2012

Chen, S., Fahmi, N. E., Nangreave, R. C., Mehellou, Y. and Hecht, S. M. 2012. Synthesis of pdCpAs and transfer RNAs activated with thiothreonine and derivatives. Bioorganic & Medicinal Chemistry 20(8), pp. 2679-2689. (10.1016/j.bmc.2012.02.024)
Thastrup, J., Rafiqi, F., Vitari, A., Pozo-Guisado, E., Deak, M., Mehellou, Y. and Alessi, D. 2012. SPAK/OSR1 regulate NKCC1 and WNK activity: analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation. Biochemical Journal 441(1), pp. 325-337. (10.1042/BJ20111879)

2011

Filippi, B. M. et al. 2011. MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. EMBO Journal 30(9), pp. 1730-1741. (10.1038/emboj.2011.78)

2010

Mehellou, Y. 2010. Phosphoramidate Prodrugs Deliver with Potency Against Hepatitis C Virus. ChemMedChem 5(11), pp. 1841-1842. (10.1002/cmdc.201000310)
Mehellou, Y., Valente, R., Mottram, H. J., Walsby, E. J., Mills, K. I., Balzarini, J. and McGuigan, C. 2010. Phosphoramidates of 2′-β-d-arabinouridine (AraU) as phosphate prodrugs; design, synthesis, in vitro activity and metabolism. Bioorganic & Medicinal Chemistry 18(7), pp. 2439-2446. (10.1016/j.bmc.2010.02.059)
Mehellou, Y., Balzarini, J. and McGuigan, C. 2010. The design, synthesis and antiviral evaluation of a series of 5-trimethylsilyl-1-β-D-(arabinofuranosyl)uracil phosphoramidate ProTides. Antiviral Chemistry & Chemotherapy 20(4), pp. 153-160. (10.3851/IMP1476)
Mehellou, Y. and De Clercq, E. 2010. Twenty-Six Years of Anti-HIV Drug Discovery: Where Do We Stand and Where Do We Go?. Journal of Medicinal Chemistry 53(2), pp. 521-538. (10.1021/jm900492g)

2009

Mehellou, Y., Balzarini, J. and McGuigan, C. 2009. Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells. Chemmedchem 4(11), pp. 1779-1791. (10.1002/cmdc.200900289)
Mehellou, Y., Balzarini, J. and McGuigan, C. 2009. An investigation into the anti-HIV activity of 2 ',3 '-didehydro-2 ',3 '-dideoxyuridine (d4U) and 2 ',3 '-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives. Organic and Biomolecular Chemistry 7(12), pp. 2548-2553. (10.1039/b904276h)

2007

Mehellou, Y., McGuigan, C., Brancale, A. and Balzarini, J. 2007. Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate "ProTide' derivatives. Biorganic and Medicinal Chemistry Letters 17(13), pp. 3666-3669. (10.1016/j.bmcl.2007.04.043)
Mehellou, Y., McGuigan, C. and Balzarini, J. 2007. The design, synthesis and Anti-HIV activity of a selected group of 2 ',3 '-didehydro-2 ',3 '-dideoxyguanosine (d4G) and 2 ',3 '-dideoxyguanosine (ddG) 'ProTide' derivatives. Antiviral Research 74(3), article number: 50. (10.1016/j.antiviral.2007.01.063)

My lab works on unravelling the roles of phosphates in cell signalling and drug discovery. To this end, we dive into cells to understand how protein kinases operate within complex signalling pathways. Such endeavour allows us to identify opportunities for discovering new medicines for diseases with unmet medical needs.

Our research is highly interdisciplinary and involves techniques and skills that span Biochemistry, Protein Crystallography, Synthetic and Medicinal Chemistry.

Detailed summary of the lab's research projects could be found here.

Further details about the lab's activities could be found at www.mehelloulab.com.

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.

I obtained my Ph.D. from the Welsh School of Pharmacy, Cardiff University. My postgraduate research was carried out in the laboratory of Prof. Christopher McGuigan. The project was on the design, synthesis and development of nucleoside analogues and their phosphate prodrugs (Phosphoramidates) as potential antiviral and anticancer therapies. During this work, I synthesised a large number of nucleoside analogues and their phosphoramidate derivatives and explored their potential as antiviral and anticancer compounds in collaboration with Prof. Jan Balzarini. I used molecular modelling as well as NMR studies to investigate the differences in biological activities seen with some of the nucleoside analogues phosphoramidates.

This was followed by a Postdoc with Prof. Sidney M. Hecht at the Biodesign Institute, Arizona State University, USA. My work then was on the development of chemical strategies that allow the incorporation of unnatural amino acids into proteins. This involved the synthesis of unnatural amino acids and ligating them to synthetic dinucleotides.

In late 2010, I took a position as an MRC Career Development Fellow with Prof. Dario R. Alessi FRS at the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU), University of Dundee. While in this position, My work was concerned with the regulation of the catalytic activity of kinases, particularly SPAK, OSR1 and MSTs, by the scaffolding protein MO25. I solved the crystal structure of the kinase MST3 in complex with MO25, which shed some light on the activation of kinases by MO25. I also worked on developing high throughput screening assays for identifying small molecules that inhibit various components of the WNK signalling pathway of which SPAK and OSR1 kinases are part of.

Honours and awards

MRC Career Development Fellowship (2010-2013).

Professional memberships

Member of the Biochemical Society.
Member of the Royal Society of Chemistry.
Member of the Biochemical Society Signalling theme Panel.

Contact Details

MehellouY1@cardiff.ac.uk
+44 29208 75821
Redwood Building, Room 2.57B, King Edward VII Avenue, Cardiff, CF10 3NB

New 3D shapes of two proteins involved in stroke and cancer have been determined