Monday, 19 September 4:00pm – 5:00pm

This seminar will be delivered in Chemistry Lecture Theatre 4 and Online Zoom Please email chemistry.researchsupport@sydney.edu.au for zoom link and password.

Speaker: Miss Eva Gao; The University of Sydney

Supervisor: Dr Yu Heng Lau

Title: Developing cyclic peptides that target ALT-positive cancers by inhibiting telomere-associated proteins

Abstract: Telomeres are the repetitive DNA sequences located at the end of chromosomes which are shortened after each cell division to restrict cellular proliferative capacity¹. For cancer cells to acquire immortality, their telomeres are constantly extended for the purpose of achieving unrestricted proliferation. While most cancers reactivate telomerase for telomere extension, a small but significant subset of cancers utilise a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT)². ALT activity is regulated by a variety of protein-protein interactions. The most well-validated target for inhibiting ALT activity is the interaction between the protein FANCM and the Bloom syndrome complex. Inhibiting this interaction eradicates the ALT process and consequently, induces toxicity towards ALT-positive cells.

Our work aims to develop macrocyclic peptide inhibitors targeting the FANCM-RMI interaction as a potential treatment for ALT-positive cancers. We employed cyclic peptide screening by mRNA display from which two cyclic peptide hits showed potent in vitro affinity (< 15 nM) towards RMI. One cyclic peptide exhibited selective toxicity towards ALT-positive cells by disrupting the FANCM-RMI interaction upon lipid-mediated delivery in cell culture. As an alternative approach, a library of peptide analogues was synthesised using the native tMM2 peptide as a starting point for rational design. A range of cyclisation chemistries with different sidechain crosslinkers was explored, along with hydrophilic tagging strategies to increase peptide solubility. In summary, our work provides insights for treating ALT cancers with peptide-based inhibitors, which is a currently underexplored area of cancer therapeutic development.

Reference:

1) Shammas, M. A. Telomeres, Lifestyle, Cancer, and Aging. Opin. Clin. Nutr. Metab. Care 2011, 14 (1), 28–34.

2) Okamoto, K.; Seimiya, H. Revisiting Telomere Shortening in Cancer. Cells 2019, 8 (2), 107.

3) Hoadley, K. A.; Xue, Y.; Ling, C.; Takata, M.; Wang, W.; Keck, J. L. Defining the Molecular Interface That Connects the Fanconi Anemia Protein FANCM to the Bloom Syndrome Dissolvasome. Natl. Acad. Sci. U. S. A. 2012, 109 (12), 4437–4442.