Identification of pharmacological tools for manipulation of myocardial creatine content
- 1 January 2010 to 31 March 2013
- Awards: Pump-priming Awards
Restoring blood flow following a heart attack saves lives, but is often associated with tissue damage due to ischaemia-reperfusion (I/R) injury. We demonstrated that elevating levels of creatine in mouse heart, by increasing activity of the creatine transporter (CrT), protects against I/R injury. This project sought to identify small molecular activators of the CrT as potential lead compounds for further development. We conducted a targeted low-throughput in vitro screen, which identified four chemically-distinct classes of CrT activators that also passed the relevant secondary screens. Of these, one compound proceeded to study of structure-activity-relationships and was tested in vivo. These compounds provided proof-of-concept for pharmacological CrT activation, but further screening is ongoing to develop lead candidates that have more desirable physicochemical properties. To do this we have recently partnered with a pharmaceutical company to gain access to their compound libraries in a newly developed high-throughput luciferase reporter screen.
Publications linked to this award:
- Zervou S, Whittington HJ, Russell AJ, Lygate CA. Augmentation of Creatine in the Heart. Mini Rev Med Chem 2016;16:19-28. PMID: 26202199.
- Lygate CA, Bohl S, ten Hove M, Faller KM, Ostrowski PJ, Zervou S, Medway DJ, Aksentijevic D, Sebag-Montefiore L, Wallis J, Clarke K, Watkins H, Schneider JE, Neubauer S. Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction. Cardiovasc Res 2012;96:466-475. PMID: 22915766
- Zervou S, Ray T, Sahgal N, Sebag-Montefiore L, Cross R, Medway DJ, Ostrowski PJ, Neubauer S, Lygate CA. A role for thioredoxin-interacting protein (Txnip) in cellular creatine homeostasis. Am J Physiol Endocrinol Metabol 2013;305:E263-270. PMID: 23715727