Dr. Mehellou has kindly shared an article on his work with us, which he has called Sneaking phosphorylated molecules into cells: a powerful strategy in drug discovery and biotechnology.
“Phosphorylated synthetic molecules and biomolecules play an important role in health and disease. They have shown great potential as therapeutics and useful biotechnological tools. However, the polar nature of phosphate groups, which limits their (passive) cellular uptake has hindered their use. To address this shortage, a number of phophate prodrugs have been developed.
The team has worked extensively on the development and application of the phophate prodrug strategy known as the ‘ProTide’ technology. This technology led to the development of a drug molecule (Sovaldi, Trademark) being approved for the treatment of Hepatitis C in 2013 whilst a number of other ‘ProTides’ are currently undergoing clinical trials for the treatment of viral infections and cancer.
Diagram showing chemical structures of two ‘ProTides’; the anti-HVC drug Sovaldi (Trademark) and the anticancer experimental drug Acelarin
We are using this phosphate prodrug technology in the discovery of new and novel therapeutics. Additionally, we are developing different versions of this prodrug approach that have more favourable in vivo properties. Also, we are exploring this technology in the intracellular delivery of both phosphorated synthetic molecules and biomolecules.
In the ‘ProTide’ approach, the 2 negative charges of the phosphate groups are masked by 2 motifs that are cleaved enzymatically inside cells to release the phosphorylated (bio)molecule.
A scheme showing the general design of phophate prodrugs, which include ‘ProTides@ and their intracellular metabolism.
We have developed an NMR_based assay for monitoring the metabolism of these ‘ProTides’ to release the phosphorylated (bio)molecules. In addition we have shown that the application of this phosphate prodrug strategy could overcome the phosphorylation rate-limiting step of many molecules. For instance, we reported the application of the ‘ProTide’ approach to a synthetic nucleoside analogue named ddU turning it from a completely inactive compound against HIV to a micromolar inhibitor of HIV replication. In fact, in some cases, the ‘ProTIde’ technology led to an impressive 9,000-fold increase in the biological activity of certain compounds. Further work also showed that the application of the ‘ProTide’ technology changes the indication of certain drug candidates. For example, the ‘ProTides’ of acyclovir, which is a known treatment of herpes simplex virus, were found to exert potent anti-HIV activity through the parent compound (acyclovir) lacked any significant activity against this enzyme.
The ‘ProTide’ technology as well as other phosphate prodrug strategies have great potential in drug discovery and in developing new tools for biotechnology. We have now accumulated great expertise in these phosphate prodrug delivery systems, which we are currently applying in the discovery of novel phosphate prodrug therapeutics and the development of new biotechnological tools.
References: ChemMedChem 2009, Org Biomol. Chem 2009, Bioorg. Med. Chem 2007 and Antimicrob. Agents Chemother. 2012