The MSCA fellowship ‘Lipopeutics’ focusses on membrane proteins – a class of proteins that make up a third of the human proteome and perform a significant role in a plethora of cellular functions including signalling, molecular transport, cellular adhesion and even cell death. This importance of membrane proteins to physiological function is exemplified by recent genomic studies identifying nearly 200,000 disease associated mutations within them. Considering this significance, enormous academic and industrial efforts have been focussed on these proteins over the past decades. However, membrane proteins still makeup nearly 60% of all current drug targets and limited novel drugs for them have been developed.
Despite the pharmaceutical impasse, significant experimental headway has been made in deciphering the underlying functional basis of these proteins. The phospholipids within the cellular membrane were long thought to ‘merely’ anchor the protein. However, advances in electron microscopy and mass-spectrometry methods have identified the lipids to be active modulators of protein function. The scientific objective of the Lipopeutics project is to rationalize this endogenous lipid modulation of protein function to design novel hydrophobic drugs.
To achieve the overarching scientific objective, the project was divided into four specific subobjectives each ascribed to its own Work Package. (1) Firstly, interaction sites of specific lipids within the protein structure needed to be identified. (2) Subsequently, the role of this lipid/binding-site in the modulation of protein function needed to be validated. (3) Then, hydrophobic lipid-like drug molecules capable of binding at the sites need to be identified. (4) Finally, the chemical structures of the identified drug molecules need to be optimized.
