Re-engineering nature using chemical and biological synthesis

In this seminar, I will outline two areas of ongoing research in my laboratory: stapled peptide therapeutics (synthetic chemistry) and encapsulin nanocompartments (synthetic biology)

The first half will cover macrocyclic stapled peptides as promising inhibitors of challenging drug targets such as intracellular protein-protein interactions. Click-cyclisation chemistry can be used to lock the conformation of a peptide, leading to improvements in proteolytic stability, target binding affinity and degree of uptake into cells. The simplicity and biocompatibility of this chemistry enables rapid identification of peptides with the desired inhibitory efficacy.

The second half will focus on a family of self-assembling bacterial proteins known as encapsulins, ideal scaffolds for in vivo compartmentalisation of enzymatic reactions. By porting the encapsulin system
from M. xanthus into S. cerevisiae, we create artificial nanocompartments in yeast which can encapsulate any protein of interest via a short targeting peptide tag. We demonstrate that
encapsulation is an effective method for extending the lifetime of unstable proteins, bringing multiple proteins into close proximity, and for conducting confined enzymatic catalysis.

1. Y. H. Lau, P. de Andrade, Y. Wu, D. R. Spring, Chem. Soc. Rev. 2014, 44, 91-102.
2. Y. H. Lau, Y. Wu, P. de Andrade, W. R. J. D. Galloway, D. R. Spring, Nat. Protoc. 2015, 10, 585-594.
3. T.W. Giessen, P. A. Silver, Nat. Microbiol. 2017, 2, 17029.
4. C. A. McHugh et al., EMBO J. 2014, 33, 1896-1911.
5. Y. H. Lau, T. W. Giessen, W. J. Altenburg, P. A. Silver, Nat. Commun., 2018, 9, 1131.