Wednesday, 10 March 11:00am – 12:00pm

This seminar will be delivered via Zoom – Please email chemistry.researchsupport@sydney.edu.au for zoom link and password.

Speaker: Dr Robert Chapman, University of New South Wales

Host: Dr Derrick Roberts

Title: Towards synthetic mimics of therapeutic proteins

Abstract: As the workhorse of biology, proteins are important therapeutic agents, but they are fragile and hard to design from scratch. Making synthetic mimics of proteins is a daunting challenge, particularly given our limited ability to precisely define the primary sequence of synthetic polymers. However, to effectively mimic protein activity a polymer need not always replicate its chemical precision and folding. Two things are needed: 1) An ability to attach peptides and other ‘binding’ motifs to precise locations to complex polymer scaffolds and 2) an ability to examine the relationship between polymer structure and function in a high throughput manner.

Our group is doing this by automation of a platform we developed for the synthesis of well-defined polymers in the presence of oxygen.^[1,2] With such systems, polymerisations can be conducted in low volume in microtiter plates (<40 µL), without any degassing, across a range of monomer families and molecular weights. In some cases conversion can even be monitored spectroscopically during polymerisation.^[2] Complex star polymers can be prepared either via polymerisation from multi-arm RAFT agents,^[3] and end-functionalised with peptides in a single droplet.^[4]

In this talk I will present some of our unpublished results from the use of this platform to design polymer mimics of the tumour necrosis factor (TNF-α) related apoptosis inducing ligand (TRAIL, also known as Apo2L or TNFSF10). This natural protein is a promising chemotherapeutic which works through oligomerisation of death receptors, but has failed in clinical trials due to instability and immunogenicity of the protein. We anticipate that our polymer mimics may offer a pathway to the design of synthetic alternatives.

 References:

[1] A. J. Gormley, J. Yeow, G. Ng, O. Conway, C. Boyer, R. Chapman, Angew. Chem. Int. Ed., 2018, 1557-1562;

[2] J. Yeow, R. Chapman, A. J. Gormley, C. Boyer, Chem. Soc. Rev., 2018. 4235–4666;

[3] J. Yeow, S. Joshi, R. Chapman, C. Boyer, Angew. Chem. Int. Ed., 2018, 1557–1562;

[4] Z. Li, S. Kosuri, H. Foster, J. Cohen, C. Jumeaux, MM Stevens, R. Chapman, AJ Gormley; J. Am. Chem. Soc., 2019, 141, 50, 19823–19830.