Youcef Mehellou

• MPharm, PhD
• Senior Lecturer at Cardiff University

The phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, in vitro metabolism, and biologi...

The activation of PINK1 by small molecules has emerged as a promising strategy in treating Parkinson's disease (PD). Recent progress in this area has raised excitement around PINK1 activators as PD treatments, and herein we offer insight into these developments and their potential to deliver much needed novel PD treatments.

Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced kinase 1 (PINK1), upon mitochondrial depolarization, is an important intermediate step in the recycling of damaged mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson's disease (PD), there has been a growing interest in small-molecule activators...

The phosphorylation of ubiquitin by the mitochondrial protein kinase PINK1, upon mitochondrial depolarization, is an important step in the repair and recycling of the mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson’s disease (PD), there has been a growing interest in small molecule modulators of PINK1-mediated mito...

STE20/SPS1‐related proline/alanine‐rich kinase (SPAK) and oxidative stress responsive 1 (OSR1) kinase are two serine/threonine protein kinases that regulate the function of ion co‐transporters through phosphorylation. The highly conserved C‐terminal (CCT) domains of SPAK and OSR1 bind to RFx[V/I] peptide sequences from their upstream ‘With No Lysin...

STE20/SPS1-related proline/alanine-rich kinase (SPAK) and Oxidative Stress Responsive 1 (OSR1) kinase are two serine/threonine protein kinase that regulate the function of ion co-transporters through phosphorylation. The highly conserved C-terminal (CCT) domains of SPAK and OSR1 bind to RFx[V/I] peptide sequences from their upstream With No Lysine...

Aryloxy triester phosphoramidate prodrugs of the monophosphate derivatives of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) were synthesized as lipophilic derivatives that can improve cell uptake. Despite the structural similarity of IPP and DMAPP, it was noted that their phosphoramidate prodrugs exhibited distinct stabili...

Isoprenoid molecules are essential in many disease-causing microorganisms, and intermediates made during their synthesis trigger immune-defence responses by γδ T cells. ‘Immunoantibiotics’ exploit this dual vulnerability. An inhibitor of the enzyme IspH combats multidrug-resistant bacteria.

Vγ9/Vδ2 T-cells are activated by pyrophosphate-containing small molecules known as phosphoantigens (PAgs). The pres-ence of the pyrophosphate group in these PAgs has limited their drug-like properties due to its instability and polar nature. In this work, we report a novel and short Olefin Grubbs metathesis-mediated synthesis of methylene and diflu...

SPAK and OSR1 are two cytoplasmic serine/threonine protein kinases that regulate the function of a series of sodium, potassium and chloride co-transporters via phosphorylation. Over recent years, it has emerged that these two kinases may have diverse function beyond the regulation of ion co-transporters. Inspired by this, we explored whether SPAK a...

COVID19 has caused thousands of deaths worldwide within a few months. The rapid spread of this virus that causes COVID19, termed SARS CoV2, has been facilitated by the lack of effective vaccines and treatments against this virus. In recent months, our team has developed a novel deep learning platform, Rosalind, for drug design and optimisation, and...

The specific targeting of protein‐protein interactions by phosphoserine‐containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinder its uptake into cells. To address these issues, we herein report the synthesis of phosphoserine aryloxy triester phosphoramidates as...

Many cellular protein-protein interactions (PPIs) are mediated by phosphoserine. The specific targeting of these PPIs by phosphoserine-containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinders its uptake into cells. To address these issues, we herein report the...

SPAK and OSR1 are two protein kinases that play critical roles in regulating ion homeostasis. They are activated under osmotic stress through phosphorylation by their upstream WNK kinases at a conserved threonine site on their T‐loops. Additionally, WNK kinases phosphorylate SPAK and OSR1 at a highly conserved serine residue on their S‐motif, the f...

The binding of SPAK and OSR1 kinases to their upstream WNK kinases is mediated by the interaction of their highly conserved SPAK and OSR1 C-terminal domain (CTD) to RFx [V/I] peptide sequences from WNK kinases. A SPAK CTD knock-in mouse, where SPAK was unable to bind WNK kinases, exhibited low blood pressure. This highlighted the inhibition of SPAK...

FULL ARTICLE could be read here: https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.8b00586 Abstract: The ProTide prodrug technology has proved very useful in the discovery of nucleotide therapeutics and has successfully led to two FDA-approved drugs. However, with the extensive application of this prodrug approach to nucleotides for nearly three...

Unmasked phohate groups of phosphotyrosine-containing molecules carry two negative charges at physiological pH, which compromise their (passive) celular uptake. Also, these phosphate groups are often cleaved off by phosphatases. Together, these ultimately limit the pharmacological efficacy of the phosphotyrosine-containing compounds. To address the...

PINK1 is a ubiquitously expressed mitochondrial serine/threonine protein kinase that has emerged as a key player in mitochondrial quality control. This protein kinase came to prominence in mid‐2000s, when PINK1 mutations were found to be causative of early‐onset Parkinson’s disease (PD). As most of these PD‐related mutations occurred in the kinase...

SPAK and OSR1 are two serine/threonine protein kinases that play important key roles in regulating ion homeostasis. Various SPAK and OSR1 mouse models exhibited reduced blood pressure. Herein, we report the discovery of Verteporfin, a photosensitizing agent used in photodynamic therapy, as a potent inhibitor of SPAK and OSR1 kinases. We show that V...

SPAK and OSR1 are two protein kinases that play important roles in regulating the function of numerous ion co-transporters. They are activated by two distinct mechanisms that involve initial phosphorylation at their T-loops by WNK kinases and subsequent binding to a scaffolding protein termed MO25. To understand this latter SPAK and OSR1 regulation...

Niclosamide is an anthelmintic drug that has mainly been used for over 50 years to treat tapeworm infections. However, with the increase in drug repurposing initiatives, niclosamide has emerged as a true hit in many screens against various diseases. Indeed, from being an anthelmintic drug, it has now shown potential in treating Parkinson's disease,...

The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were...

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein repo...

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 in treating neurodegenerative diseases such as PD. Herein, we show that the anthelmintic drug niclosamide and its analogues ar...

Since the discovery of WNK mutations causing an inherited form of hypertension in humans, there has been an increasing interest in targeting WNK-signaling as a novel strategy for modulating blood pressure. This notion is now supported by numerous mouse models with impaired WNK-signaling that exhibit reduced blood pressure. Biochemical analyses of t...

The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this approach, the hydroxyls of the monophosphate or monophosphonate groups are masked by an aromatic group and an amino acid ester moiety, which are enzymatically cleaved-off inside cells to...

SPAK and OSR1 are two protein kinases that emerged as attractive targets in the discovery of novel antihypertensive agents due to their role in regulating electrolyte balance in vivo. In this work, we report on the identification of an allosteric pocket on their highly conserved C-terminal domains, which influences their kinase activity. Also, we s...

Since loss of function mutations of PINK1 lead to early-onset Parkinson's disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activ...

The cover picture shows the chemical structure of HK01, a small molecule that binds the scaffolding protein MO25 and inhibits its binding to SPAK/OSR1 kinases, which subsequently reduces their catalytic activity. Such binding is translated into reduced phosphorylation and manipulation of the activities of a series of sodium, potassium and chloride...

The binding of the scaffolding protein MO25 to SPAK and OSR1 protein kinases, which regulate ion homeostasis, causes up to 100-fold increase in their catalytic activity. Since various animal models showed that the inhibition of SPAK and OSR1 lowers blood pressure, we herein present a novel indirect approach for inhibiting SPAK and OSR1 kinases by t...

A new series of chiral ferrocene derivatives containing both a hydroxyalkyl group and a thyminyl group on one cyclopentadienyl ring have been synthesised in order to probe structure activity relationships in cancer cell-line cytotoxicities. Stereoisomers of enantiomeric pairs of these so-called ferronucleosides have been studied and characterised b...

Nucleoside monophosphates and monophosphonates have been known for a long time to exert favorable pharmacological effects upon intracellular delivery. However, their development as drug molecules has been hindered by the inherent poor drug-like properties of the monophosphate and monophosphonate groups. These include inefficient cellular uptake and...

The masking of nucleoside phosphate and phosphonate groups by an aryl motif and an amino acid ester, nowadays known as the 'ProTide' technology, has proven to be effective in the discovery of nucleotide therapeutics. Indeed, this technology, which was invented by Chris McGuigan in the early 1990s, has inspired the discovery of two FDA-approved anti...

Examples of organometallic compounds as nucleoside analogues are rare within the field of medicinal bioorganometallic chemistry. We report on the synthesis and properties of two chiral ferrocene derivatives containing both a nucleobase and a hydroxyalkyl group. These so-called ferronucleosides show promising anticancer activity, with cytostatic stu...

The WNK [with no lysine (K) kinase]-SPAK/OSR1 signalling pathway plays an important role in controlling mammalian blood pressure by modulating the activity of ion co-transporters in the kidney. Recent studies have identified hypertension Gordon's syndrome patients with mutations in either Cullin-3 (CUL3) or the BTB-protein Kelch-like 3 (KLHL3). CUL...

The MO25 scaffolding protein operates as critical regulator of a number of STE20 family protein kinases (e.g. MST and SPAK isoforms) as well as pseudokinases (e.g. STRAD isoforms). To better understand how MO25 interacts and stimulates the activity of STE20 protein kinases, we determined the crystal structure of MST3 catalytic domain (residues 19-2...

Mutations in the WNK [with no lysine (K) kinase] family instigate hypertension and pain perception disorders. Of the four WNK isoforms, much of the focus has been on WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). WNK isoforms phosphorylate and activate the related SPAK (SPS1-related proline...

Mouse protein-25 (MO25) isoforms bind to the STRAD pseudokinase and stabilise it in a conformation that can activate the LKB1 tumour suppressor kinase. We demonstrate that by binding to several STE20 family kinases, MO25 has roles beyond controlling LKB1. These new MO25 targets are SPAK/OSR1 kinases, regulators of ion homeostasis and blood pressure...

INX-08189: A new sensation! The hepatitis C virus (HCV) antiviral clinical candidate INX-08189, which is a phosphoramidate prodrug of 2′-C-methylguanosine, has recently entered human clinical trials. This anti-HCV nucleoside-derived phosphoramidate, the third of its kind currently under clinical evaluation, has an impressive overall pharmacological...

Nucleoside analogues always require phosphorylation to be active. This appears to be a particular limitation for uridine-based nucleosides. Our ProTide method allows the direct use of masked membrane-soluble preformed nucleoside phosphates, bypassing the need for the initial phosphorylation step. We herein applied it to some novel 5-trimethylsilyl...

2'-Beta-D-arabinouridine (AraU), the uridine analogue of the anticancer agent AraC, was synthesized and evaluated for antiviral activity and cytotoxicity. In addition, a series of AraU monophosphate prodrugs in the form of triester phosphoramidates (ProTides) were also synthesized and tested against a range of viruses, leukaemia and solid tumour ce...

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Prodrug technologies aimed at delivering nucleoside monophosphates into cells (protides) have proved to be effective in improving the therapeutic potential of antiviral and anticancer nucleosides. In these cases, the nucleoside monophosphates are delivered into the cell, where they may then be further converted (phosphorylated) to their active spec...

As part of our studies on the anti-HIV activities of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) and their 'ProTides', we have prepared and evaluated the anti-HIV activity of a range of d4U and ddU aryl triester phosphoramidates. Besides elucidating SAR characteristics, we performed molecular modelling studies on both d4U...

We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the mo...

Over the last 20 years, the field of anti-HIV drug development has arguably been the most fruitful within the many ongoing drug discovery programs. This is reflected by the fact that there are now more drugs approved for HIV than for all other viral infections taken together. The use of these drugs, mostly in combinations, has considerably improved...