Poster Presentation International Peptide Symposium 2023

Spider beta-hairpin peptide engineered to target protein:protein interactions, reach the cytosol, and kill cancer cells (#373)

Ferran Nadal-Bufi 1 2 , Lai Y Chan 2 3 , Hadi H Mohammad 4 , Jody M Mason 4 , Carlos Salomon 5 , Andrew Lai 5 , Erik W Thompson 1 , David J Craik 2 3 , Quentin Kaas 2 3 , Sonia Troeira Henriques 1 2
  1. School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Woolloongabba, QLD, Australia
  2. ARC Centre of Excellence for Innovations in Peptide and Protein Science, Brisbane, QLD, Australia
  3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  4. Department of Biology and Biochemistry, University of Bath, Bath , United Kingdom
  5. The University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia

Peptides hold great potential as a novel therapeutic modality to inhibit intracellular protein:protein interactions (PPIs) involved in cancer. A major and common challenge with peptide-based drugs is ability to enter cells and reach the cytosol, where many cancer targets are located. Lactate dehydrogenase 5 (LDH5) is a cytosolic enzyme overexpressed in aggressive and metastatic tumors and is an attractive target for anticancer therapy. Combining rational and computer-based approaches, we designed a cyclic beta-hairpin peptide with high affinity towards a β-sheet region that is involved in PPIs required for the enzymatic activity of LDH5 [1]. In addition, we reengineered the lead LHD5-inhibitor peptide to be cell penetrating and non-membrane disruptive. Using bioassays and proteomics we confirmed that the lead peptide, [R/r]cGmC9, inhibits LDH5 in the cytosol, modulates cancer metabolism and kills cancer cells [2]. This is the first non-competitive peptide-based inhibitor of LDH5 with activity in cancer cells. These studies demonstrate the potential of using peptides as inhibitors of intracellular PPIs relevant for cancer pathways and shows that active peptides can be rationally designed to improve their cell permeation. The success of this approach is relevant not only because it modulates the activity of a very important cancer target, but also because it tackles two challenges in the development of peptide-based drugs: the modulation of PPIs involved in cancer, and the efficient delivery of peptides into the cytosol.

  1. Nadal-Bufi F., Mason J. M., Chan L. Y., Craik D.J., Kaas Q., Henriques S.T. (2021) Designed beta-harpins inhibit LDH 5 oligomerization and emzymatic activity, J Med Chem, 64, 3767-3770.
  2. Nadal-Bufi F. Chan L.Y., Mohammad H.H., Mason, J.M., Salomon C., lai A., Thompson E.W., Craik D.J., Kaas Q., Henriques S.T. (2022) Peptide-based LDH5 inhibitors enter cancer cells and impair proliferation, Cell Mol Life Sci., 79:606.