Blocking substrate recruitment by DHHC-protein acyl transferase enzymes for therapeutic gain
Researchers at the University of Dundee have discovered and validated a novel approach for targeting an important class of enzymes with wide activity and linkage to disease.
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. Thus far, drug discovery efforts with DHHC-PATs have focused on trying to identify isoform-specific active site inhibitors of protein palmitoylation. As yet, however, no such molecules have been reported. A potential drawback of trying to develop inhibitors that selectively bind at the catalytic sites of individual DHHC-PATs is that they will block palmitoylation not just of particular proteins of interest but the entire ensemble of substrate proteins for the enzyme being targeted. To overcome this problem, 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.
The University is seeking a commercial partner for this technology and contact is welcomed from organisations interested in developing, licensing or exploiting this opportunity.
IP Status: The technology is protected by patent application (PCT/GB2017/051055).
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