Wednesday, 13 September 11:00am – 12:00pm

This seminar will be delivered in Chemistry Lecture Theatre 4

Speaker: Dr Ole Tietz, Macquarie University

Host: Dr Yu Heng Lau

Title: Development of intracellular therapeutics using tricyclic cell-penetrating peptides

Abstract: The intracellular environment hosts a large number of disease-relevant human proteins. Targeting these with internalized antibodies would allow therapeutic modulation of hitherto undruggable pathways, such as those mediated by protein–protein interactions. However, one of the major obstacles in intracellular targeting is the entrapment of biomacromolecules in the endosome.

We developed an approach to delivering antibodies and antibody fragments into the cytosol and nucleus of cells using trimeric cell-penetrating peptides (CPPs). Our studies identify a tricyclic Tat peptide construct that enables intracellular delivery of functional immunoglobulin-G antibodies and Fab fragments via non-toxic, endocytic mechanisms at effective concentrations as low as 1 μM. Biomacromolecules bind intracellular cytosolic proteins (b-actin) and nuclear proteins (Histone H2B) live cells.¹

In addition, we demonstrate delivery of cargos in live primary neuronal cells, as well as human brain organoids. This delivery system enables functional interaction of antibodies with cytosolic and nuclear proteins and is important step towards the development of intracellular immunotherapies with potential to treat neurodegenerative diseases characterized by intraneuronal deposits of aggregate protein.

References:

1. O. Tietz, F. Cortezon-Tamarit, R. Chalk, S. Able, K. A. Vallis, Nat. Chem. 2022, 14, 284-293.

Bio: Dr Ole Tietz is a Research Fellow at Macquarie Medical School and based at the Dementia Research Centre where he leads the Chemistry Group. Ole has a background in Chemistry and completed his PhD at the University of Alberta, Canada, in 2015 under the supervision of Prof Frank Wuest. Ole held post-doctoral fellowships at the University of Cambridge, Department of Neurosciences, and the University of Oxford, Department of Oncology. Ole is interested in developing novel drugs for the diagnosis and therapy of neurodegenerative diseases. This includes the rational design of small molecules; the design and study of peptide complexes; the engineering and modification of antibodies; and post-translational modification of proteins to understand and treat a variety of Dementias. Ole’s research program is support by funding from the NHMRC and ARC.