Mehellou, Youcef - Cardiff University - School of Pharmacy and Pharmaceutical Sciences

个人简介

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.

研究领域

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.

近期论文

查看导师新发文章（温馨提示：请注意重名现象，建议点开原文通过作者单位确认）

Kadri, H.et al. 2017. Towards the development of small molecule MO25-binders as potential indirect SPAK/OSR1 kinase inhibitors. Chembiochem (10.1002/cbic.201600620) pdf Kedge, J.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) Mehellou, Y. 2016. The ProTides boom. Chemmedchem 11(11), pp. 1114-1116. (10.1002/cmdc.201600156) Nguyen, H.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) 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) pdf Mehellou, Y.et al. 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) pdf Chen, S.et al. 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.et al. 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) pdf Filippi, B.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) Mehellou, Y. 2010. Phosphoramidate Prodrugs Deliver with Potency Against Hepatitis C Virus. ChemMedChem 5(11), pp. 1841-1842. (10.1002/cmdc.201000310) Mehellou, Y.et al. 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)