Synthesised protein for angiogenesis control
The benefits of collaborative research are much in evidence at the University of Dundee, UK. Experts in molecular modelling, synthesis and biological testing have synthesised a recently discovered molecule that promotes angiogenesis and wound healing. The work could be turned to numerous pharmacological applications, say the researchers.
David Norman and Rodolfo Marquez, lecturers in the university’s division of biological chemistry, now housed in the life sciences faculty, have synthesised a mimetic for the protein mobility stimulating factor (MSF), discovered by colleagues in the Dundee dental school. MSF is found in foetal tissue, tissue around wounds, and is expressed by some tumours.
The activity of MSF has been pinpointed to a short peptide sequence in the protein. But even short peptides present problems when designing mimetics, says Norman. ’Peptides can adopt a wide range of backbone conformations let alone the conformational flexibility of the side chains,’ he said. The peptide sequence turned out to be part of a tight turn within the protein module structure, with a section of it making direct contacts with the main body of the protein. A literature search found no peptidomimetic structures, but did provide a couple of leads for the generation of molecular frameworks.
Norman constructed computer models of the basic compound and investigated its 3D conformation using ab initio chemical modelling techniques. After working through possible variations and various cycles of optimisation, the researchers decided that a benzodiazepine-like unit would provide a suitable starting point for lead development.
The target benzodiazepine unit was synthesised in racemic form, and the compound tested by measuring its effect on cells migrating through a type I collagen matrix. ’The results were remarkable in showing that even the racemic version of our prototype compound was able to perform at over 50 per cent of activity shown by MSF at concentrations as low as 75nM,’ Norman told Chemistry World, admitting that the state of IP protection on this work prevents the release of further details.
Drugs designed as either agonists or antagonists to MSF could have uses in treating difficult to heal wounds, reducing scar tissue, treating a variety of vascular diseases and, in the case of an antagonist, stopping the growth and spread of certain tumours.
’This work is just one example of the collaborations that are developing within the school of life sciences and associated faculties such as medicine and dentistry,’ said Norman. ’Funding to develop this most promising lead as a pharmaceutical agent and chemical genomic tool is being actively pursued.’