Posted on 19 June 2018
Researchers in the departments of Chemistry and Biology have developed a breakthrough new protein chemistry technique that will help further research into the deadly tropical disease Leishmaniasis, which claims up to 50,000 lives a year.
The ultra-mild ‘bioconjugation’ method enables the attachment of small molecules to delicate biological machinery, including a protein from the surface of the Leishmania parasite, which is essential for infection.
The new method was developed by an interdisciplinary team at the University of York led by Dr Martin Fascione. Taking inspiration from the well-known classical organic synthetic “cross aldol” reaction first studied in 1881, and its modern reinvention in the presence of small molecule organocatalysts, the team designed a potent ‘protein cross-aldol’ reaction capable of modifying proteins in minutes at neutral pH. They refer to their approach as ‘OPAL’ (Organocatalyst-mediated Protein Aldol Ligation).
OPAL can chemically modify a range of proteins with minimal change to their natural function. Using this new technique, multiple small molecule cargoes can be attached including cancer-targeting agents and fluorescent tags.
The methodology was showcased in the ‘chemical mimicry’ of an essential protein found on the surface of Leishmania parasites, which are spread by sandflies and the causative agent of the tropical disease Leishmaniasis which affects 12 million people worldwide.
Dr Fascione said:
'The key to the OPAL method is that it allows modification of proteins under mild biologically compatible conditions, meaning that their natural function is more likely to be retained. This has proved especially powerful for studying the Leishmania surface protein as it is naturally modified within the parasite with two different small molecules which are essential for infection, but the reason for this modification is not absolutely clear due to the challenges of working with the parasite in the lab. In this study we were able to use our chemistry to recreate these natural modifications in a test tube, providing an abundance of the protein in its natural form, which enabled us to begin to explore why these modifications are so important for infection.'
The research was published in Chemical Science, the flagship journal of The Royal Society of Chemistry.