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On the 'trail' for new anti-cancer drugs

A European project is looking to exploit activation of certain cell death pathways in tumour cells. Leaving healthy cells intact, the therapeutic potential of this approach is enormous.
On the 'trail' for new anti-cancer drugs
Conventional anti-cancer therapies have utilised the binding of the protein —tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) — to certain death receptors. However, these pharmaceutical strategies have not shown significant survival benefits so far.

The EU-funded 'An integrated peptide and foldamer chemistry approach towards pro-apoptotic trail mimetics' (FOLDAPOP) project investigated and developed the use of peptidomimetic foldamers to selectively activate cell death in cancerous cells. These novel peptide-based drugs should selectively bind to the death receptors (DR4 and DR5) to activate the TRAIL pathway. Besides being less immunogenic, they will have the added advantage of easy production and storage.

Scientists synthesised several analogues of TRAILmim (M1c) to investigate the structural requirements of DR5-binding peptides using techniques such as macrocyclisation and solid-phase peptide synthesis (SPPS). Results revealed the importance and sensitivity of the disulphide bridges in M1c for DR5 binding and desired bioactivity. Another analogue of M1C was subsequently prepared showing promising DR5-binding properties when tested using the surface plasmon resonance (SPR) method.

Researchers developed an innovative solid-phase synthesis (SPS) methodology to selectively attach DR5-binding peptides including M1c onto short-chain multivalent helical foldamers. Results showed good purity and yield with increasing multivalency possibly contributing to better bioactivity and specificity to DRs.

FOLDAPOP members selected helix-forming urea/gamma-amide oligomer hybrids to construct on-bead foldamer libraries and successfully synthesised 16 new monomers. Several model hybrids were subsequently synthesised with method validation performed on azido succinimidyl carbamates and Fmoc-gamma-AA. From several solid supports, the TentaGel (polyoxyethylene-grafted polystyrene) was selected for one-bead one-compound (OBOC) library construction.

The complex object parametric analyser and sorter (COPAS) was used to screen compounds with varying Tryptophan-type residue position for binding to the fluorescently labelled DR5 receptor. The tandem mass spectrometry matrix-assisted laser desorption/ionisation method was extremely sensitive, providing detailed information on single beads containing just 40 picomol of the compound. Nine shortlisted compounds were then converted into dimers to increase bioactivity against cancer cells; this offered promising preliminary results. SPR measurements are ongoing to validate results and confirm the binding of dimeric foldamers to DR5.

Project outcomes have demonstrated the feasibility of using on-bead libraries of hybrid foldamers to shortlist promising compounds and produce single beads with high DR affinity. This will not only attract research investment in foldamers as drug targets, but could also find applications in other diseases besides cancer.

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