Therapeutic targeting of protein S-acylation for the treatment of disease

The post-translational modification protein S-acylation (commonly known as palmitoylation) plays a critical role in regulating a wide range of biological processes including cell growth, cardiac contractility, synaptic plasticity, endocytosis, vesicle trafficking, membrane transport and biased-receptor signalling. As a consequence, zDHHC-protein acyl transferases (zDHHC-PATs), enzymes that catalyse the addition of fatty acid groups to specific cysteine residues on target proteins, and acyl proteins thioesterases, proteins that hydrolyse thioester linkages, are important pharmaceutical targets. At present, no therapeutic drugs have been developed that act by changing the palmitoylation status of specific target proteins. Here, we consider the role that palmitoylation plays in the development of diseases such as cancer and detail possible strategies for selectively manipulating the palmitoylation status of specific target proteins, a necessary first step towards developing clinically useful molecules for the treatment of disease.