Dr Youcef Mehellou

Darllenydd

Ysgol Fferylliaeth a Gwyddorau Fferyllol

: MehellouY1@caerdydd.ac.uk
: +44 29208 75821
: Adeilad Redwood , Ystafell 2.57B, Rhodfa'r Brenin Edward VII, Caerdydd, CF10 3NB

: Ar gael fel goruchwyliwr ôl-raddedig

I joined School of Pharmacy and Pharmaceutical Sciences at Cardiff University as a Lecturer in Medicinal Chemistry in January 2017. 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, University of Dundee, until March 2013 when I joined the University of Birmingham.

I have a major interest in the discovery of chemical strategies that manipulate signal transduction. My current projects fall under two major themes:

Development of new therapeutic phosphate prodrugs
Discovery of therapeutic protein-protein interaction inhibitors

Lab Webpage: www.mehelloulab.com

Qualifications

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

Date
Type

2024

Xu, Q., Sharif, M., James, E., Dismorr, J. O., Tucker, J. H. R., Willcox, B. E. and Mehellou, Y. 2024. Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells †. RSC Medicinal Chemistry 15(7), pp. 2462-2473. (10.1039/d4md00208c)

2023

Mehellou, Y. 2023. Parkinson's disease: are PINK1 activators inching closer to the clinic?. ACS Medicinal Chemistry Letters 14(7), pp. 870-874. (10.1021/acsmedchemlett.3c00070)
Lambourne, O. A. et al. 2023. PINK1-Dependent mitophagy inhibits elevated ubiquitin phosphorylation caused by mitochondrial damage. Journal of Medicinal Chemistry 66(11), pp. 7645-7656. (10.1021/acs.jmedchem.3c00555)

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)

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. 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)
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)

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 research is highly interdisciplinary and involves techniques and skills that span Synthetic and Medicinal Chemistry, Biochemistry and Crystallography. Current active projects:

Design, synthesis and biological evaluation of phosphate prodrugs

Developing platform technologies that allow the delivery of phosphorylated molecules into cells is of great interest to us. We have great expertise in the synthesis and application of the phosphoramidate technology ('ProTide') [see Mehellou et. al. 2009, ChemMedChem, 4, 1779-91], which has been shown to be an effective technology in delivering nucleoside analogues monophosphates into cells. The application of this technology can turn inactive nucleoside analogues into active ones. Largely, this technology is known to significantly improve the pharmacological activity of nucleoside analogues.

Our current efforts are focused on introducing new chemical modifications to the 'ProTide' technology to achieve tissue-specific delivery. Additionally, we are applying the 'ProTide' technology to discover nucleotide therapeutics that can treat diseases with unmet medical needs.

Discovery of therapeutic protein-protein interaction inhibitors

We employ chemical approaches to decode cellular signal transduction networks. Currently, we are in the process of translating our current understanding of the regulation of SPAK and OSR1 kinases into small molecules that manipulate their function. Current efforts include designing and synthesising a series of small molecules that have the potential to manipulate SPAK/OSR1 signalling. To achieve this, we are using crystallography, virtual screening, chemical synthesis and biological testing of the synthesised compounds.

Further details can be found @ http://mehelloulab.wixsite.com/lab1

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, Youcef’s work was concerned with the regulation of the catalytic activity of kinases, particularly SPAK, OSR1 and MSTs, by the scaffolding protein MO25. Youcef solved the crystal structure of the kinase MST3 in complex with MO25, which shed some light on the activation of kinases by MO25. Youcef 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.

Anrhydeddau a dyfarniadau

MRC Career Development Fellowship (2010-2013).

Aelodaethau proffesiynol

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

Mae siapiau 3D newydd o ddau brotein sy'n gysylltiedig â strôc a chanser wedi'u pennu