Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 7, Pages 3767-3779Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01898
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Funding
- Australian Research Council (ARC) [FT150100398]
- Queensland University of Technology Postgraduate Research Award Scholarship
- Biotechnology and Biological Sciences Research Council [BB/T018275/1, BB/R017956/1]
- Cancer Research UK [A26941]
- Australian Government
- ARC Australian Laureate [FL150100146]
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science [CE200100012]
- BBSRC [BB/T018275/1, BB/R017956/1] Funding Source: UKRI
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Through rational and computer-based approaches, peptidic sequences with high affinity towards a beta-sheet region were identified and grafted into a cyclic cell-penetrating scaffold to inhibit LDH5 activity effectively. This approach of targeting an interface important for LDH5 function challenges the landscape of traditional small-molecule drug discovery programs.
Lactate dehydrogenase 5 (LDH5) is overexpressed in metastatic tumors and is an attractive target for anticancer therapy. Small-molecule drugs have been developed to target the substrate/cofactor sites of LDH5, but none has reached the clinic to date, and alternative strategies remain almost unexplored. Combining rational and computer-based approaches, we identified peptidic sequences with high affinity toward a beta-sheet region that is involved in protein-protein interactions (PPIs) required for the activity of LDH5. To improve stability and potency, these sequences were grafted into a cyclic cell-penetrating beta-hairpin peptide scaffold. The lead grafted peptide, cGmC9, inhibited LDH5 activity in vitro in low micromolar range and more efficiently than the small-molecule inhibitor GNE-140. cGmC9 inhibits LDH5 by targeting an interface unlikely to be inhibited by small-molecule drugs. This lead will guide the development of new LDH5 inhibitors and challenges the landscape of drug discovery programs exclusively dedicated to small molecules.
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