Scientists at the University of Dundee have identified a `molecular commando’ which can be stealthily deployed to activate a hypoxic response, a process which can help to fight a range of conditions including stroke, angina, colitis and brain injuries.
A Dundee team led by Professor Alessio Ciulli have used pioneering techniques to develop a `small molecule’ chemical probe called VH298, which offers highly targeted access to the parts of the cell which regulate hypoxia, known as the hypoxic signalling pathway.
“Using a small molecule like this offers a highly targeted option to control the hypoxic pathway, and one which can sneak in under the cell’s natural defences to perform its work, a bit like a molecular commando,” said Professor Ciulli.
The research has been published in Nature Communications.
Pedro Soares and Julianty Frost, two PhD students, explained their contribution to the research. Pedro synthesized the compounds and performed the biophysical characterisation while Julianty performed the majority of the cell work. “This compound was designed to target a specific protein-protein interaction on the hypoxia pathway. There is no known compound that has targeted this interaction with enough potency in cells,” explained Pedro. “Many of the previous ways to study this pathway have caused off-target effects so we have worked for a number of years refining to make a compound that is specific, selective, permeable, potent and non-toxic. All the desired qualities you want in the early stages of drug design.”
The use of small molecules like this is a growing area of drug development, offering the prospect of highly specific treatments for many conditions. Successfully identifying and developing suitable small molecules, however, is extremely complex.
“We have been able to develop this project due to the world-class expertise we have at Dundee, bringing together people from different laboratories and areas of knowledge,” said Professor Ciulli. “So in my lab we work on design and studying how this types of molecules work but we are also able to call on scientists like Sonia Rocha, with expertise in oxygen sensing pathways, Doreen Cantrell, whose world-renowned work includes the role of hypoxia in immune cells, and Kevin Read in our Drug Discovery Unit, who has helped us maximise the drug-like properties of the molecule.
“It is this combination of world-class work that has helped make Dundee the top-ranked place in the UK for biological sciences research.”
Pedro and Julianty are keen to point out that as exciting as this compound may be, this is just the beginning and further study is required. “Currently, it is a very useful tool for the study of the hypoxia pathway,” said Julianty. “It allows scientists to tackle new questions in new ways, which could lead to unforeseen discoveries.” By sharing the information about the molecule with the wider scientific community in the newly established ‘Chemical Probes Portal’ (http://www.chemicalprobes.org/), it is hoped that it will speed up the advances in knowledge in the hypoxia field and beyond. “We have had interest from other research groups in the country with further work already underway,” commented Julianty.
Professor Ciulli was named earlier this year as one of Europe’s rising stars of science when he was awarded the 2016 MedChemComm Emerging Investigator Lectureship. He was also awarded the Capps Green Zomaya Memorial Award by the Royal Society of Chemistry.
Pedro Soares is from the Ciulli lab and funded by Fundação para a Ciência e a Tecnologia: FCT. Julianty Frost a joint PhD student between the Ciulli and Rocha labs and is funded by the Wellcome Trust.