Wednesday, 9 September 2020. 11am – 12pm.

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

Elisabeth Tondl, PhD Candidate, School of Chemistry.

Host:  Prof Trevor Hambley

Modulating prodrug selectivity for prostate cancer: Design, synthesis, and testing of a modified peptide vehicle

Precision oncology approaches in prostate cancer treatment offer a complementary approach to genomics by targeting molecular phenotypes of an individual’s cancer, such as membrane transporter or protease expression. Prostate-specific antigen, a protease expressed by prostate cells, has played a key role in the diagnosis, stratification, and monitoring of prostate cancer patients. It is also a potential target for delivering drugs to prostate cancer using a protease-based activation strategy, involving the activation of a prodrug when it is cleaved by a protease.

The HSSKLQ (HisSerSerLysLeuGln) peptide sequence is readily cleaved by active prostate-specific antigen, but not by other proteases common in human serum. It has been used to deliver drugs to prostate cancer cells in vitro and in vivo, but off-target activation has been observed. Modification of the HSSKLQ sequence to reduce off-target activation of the peptide-drug conjugates is one approach to improve the delivery of chemotherapeutics and radiotheranostics to prostate cancer cells.

Computational molecular modelling was used to design modifications to the HSSKLQ sequence in order to decrease off-target activation of a drug-HSSKLQ conjugate, and to enhance interactions with prostate-specific antigen. Modified HSSKLQ-based peptides were conjugated to fluorescent tags to enable tracking of their in vitro localisation of the conjugates using fluorescence microscopy. Biological assays revealed that the modified peptide sequence is cleaved by prostate-specific antigen, resulting in release of the model active drug. In vitro fluorescence imaging indicated low uptake of the released drug in cultured cells. Future directions for this work will be discussed.