Blocking Substrate Recruitment

About

About Numerous physiological processes including cell growth, cardiac contractility, synaptic plasticity, endocytosis, vesicle trafficking and biased-receptor signaling are regulated by protein S-acylation. As a consequence DHHC-protein acyl transferases (DHHC-PATs), enzymes that attach fatty acids to specific Cysteine residues in target proteins, are of substantial interest to the pharmaceutical industry. Researchers at the University of Dundee have developed a novel approach where recruitment of specific substrates to particular DHHC-PATs is blocked, preventing palmitoylation of the target protein. Using proprietary technologies developed by researchers at the University of Dundee, the molecular basis of substrate recruitment by different DHHC-PAT enzyme isoforms has been understood. Using this knowledge, assays compatible with high-throughput screening are currently being developed that will allow future identification of molecules that abrogate specific enzyme-substrate protein-protein interactions. Partner organisations with expertise in drug screening and development are sought. Using heart disease as an exemplar, the researchers have developed a new approach for selective activation of the cardiac Na-K-ATPase by blocking palmitoylation of the pump’s accessory protein phospholemman (PLM). Stimulation of the cardiac Na pump will have therapeutic benefit in the treatment of ischaemia/reperfusion injury, hypertrophy and heart failure by limiting intracellular Na overload. Other target proteins currently being worked on by the Dundee group include glucose transporter 4 (associated disease, diabetes), CD36 (metabolic syndrome) and ras (cancer). Expressions of interest in these projects would be welcome. Alternatively, novel targets known to undergo palmitoylation can be nominated by companies for the Dundee group to work on with a view to developing a bespoke assay for screening purposes. Key Benefits Novel target for heart failure therapeutics Assay available for high throughput screening Applications Applications in transformational drug discovery Beneficial in the treatement of ischaemia/reperfusion injury, hypertrophy and heart failure  IP Status This technology is protected by patent application (GB 1606376.0).