About the Project
In 2009 we developed a revolutionary new polymer-based method (SMALP), also known as a molecular cookie cutter, to produce the membrane proteins. The method negates the problematic use of detergents in making membrane proteins, instead encapsulating them, complete with a portion of phospholipid membrane in a 10 nm diameter nanodisc. We have shown that the SMALP methods in generically applicable to a wide range of membranes proteins ranging from G-protein coupled receptors (GPCRs) to receptors used to allow viruses (like COVID-19) entry to cells. The resulting preparations show a high degree of activity and a stability that is substantially enhanced over detergent purified samples. These observations have made the method an ideal one for use in drug discovery meaning that there has been significant interest from a wide range of pharmaceutical companies who see it as a way of relieving a crucial bottleneck in their therapeutic discovery pipelines. In this project we will work with Domainex Ltd to develop the SMALP for use in their therapeutic discovery campaigns pipelines involving GPCRs.
This project will include:
1) Using our SMALP system to produce membrane proteins that are drug targets
2) Developing improved SMALP systems that allow a wider range of drug targets to be produced and tested.
3) Studying the structure and function of these proteins using a range of techniques including SPR and Cryo-EM
Together these elements will show that polymer-solubilisation renders otherwise intractable drug targets accessible to the biophysical and structural methods needed to drive therapeutic discovery programs. In particular, Domainex is developing a generic biophysical drug discovery platform for GPCR targets, and the neurotensin 1 receptor can be used as an early test case.
Encapsulated membrane proteins: A simplified system for molecular simulation. Lee SC, Khalid S, Pollock NL, Knowles TJ, Edler K, Rothnie AJ, R T Thomas O, Dafforn TR. Biochim Biophys Acta. 2016 Oct;1858(10):2549-2557.
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