Proefschrift
Thermostable Nanodiscs for the development of novel biopharmaceuticals
Nanodiscs are small, disc-shaped structures designed to mimic biological cell membranes, composed of a lipid bilayer stabilized by scaffold proteins. Membrane proteins play crucial roles in essential processes such as nutrient and waste transport, molecular recognition, and cell signalling, making them key targets in drug development.
- Auteur
- T.G.J. Knetsch
- Datum
- 17 oktober 2024
- Links
- Thesis in Leiden Repository
Nanodiscs offer a versatile platform for investigating these proteins under near-native conditions, providing valuable insights into their structure and function.Inspired by the specialized membranes of thermophilic archaea—microorganisms that live in extreme temperatures—my thesis explores whether implementation of lipid structural features adapted from these organisms can enhance the thermal stability of Nanodiscs, and the proteins they encapsulate. My findings showed that the fatty acid tails can be tuned to increase the stability of Nanodiscs and membrane proteins like CYP3A4, a detoxification enzyme in the human body. The lipids help to maintain protein folding at higher temperatures, which is crucial for activity. Additionally, I discovered that the lipid composition of Nanodiscs affects how well drugs and small molecules bind to Nanodisc membranes, providing key insights for developing drug screening methods for membrane protein targets.Stable Nanodiscs could also improve vaccines by making them more heat-resistant, reducing the need for cold storage and expanding access to vaccines in low-resource areas. Additionally, this could also extend the circulation time of therapies in the body, which could be beneficial for small molecule drug delivery or to give the immune system more time to respond to vaccine antigens delivered by Nanodiscs.In summary, my research shows how nature-inspired lipid adaptations can be harnessed to improve artificial membranes for biotechnology applications.