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Updated: Nov 11, 2025

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
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Designed β-Hairpins Inhibit LDH5 Oligomerization and Enzymatic Activity

Ferran Nadal-Bufi1, Jody M Mason2, Lai Yue Chan3

  • 1School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, Queensland 4102, Australia.

Journal of Medicinal Chemistry
|March 25, 2021
PubMed

Insights

Researchers developed a novel peptide inhibitor, cGmC9, targeting Lactate dehydrogenase 5 (LDH5) in metastatic tumors. This peptide offers a new strategy for anticancer therapy by inhibiting LDH5 activity more effectively than small-molecule drugs.

Area of Science:

  • Biochemistry
  • Oncology
  • Drug Discovery

Background:

  • Lactate dehydrogenase 5 (LDH5) is overexpressed in metastatic tumors, making it a potential therapeutic target.
  • Current small-molecule inhibitors targeting LDH5 have not reached clinical application, necessitating alternative strategies.

Purpose of the Study:

  • To identify and develop novel peptide-based inhibitors targeting LDH5.
  • To explore alternative drug discovery approaches beyond small molecules for LDH5 inhibition.

Main Methods:

  • Utilized rational and computer-based approaches to identify high-affinity peptidic sequences targeting LDH5.
  • Grafted identified sequences into a cyclic cell-penetrating β-hairpin peptide scaffold to enhance stability and potency.
  • Assessed the inhibitory activity of the lead peptide, cGmC9, against LDH5 in vitro.

Main Results:

  • Identified peptidic sequences targeting a β-sheet region crucial for LDH5 protein-protein interactions.
  • The lead peptide, cGmC9, demonstrated low micromolar inhibition of LDH5 activity in vitro.
  • cGmC9 exhibited superior inhibition compared to the small-molecule inhibitor GNE-140, targeting a novel interface.

Conclusions:

  • Peptide-based inhibitors like cGmC9 represent a promising alternative to small molecules for targeting LDH5.
  • cGmC9's unique inhibition mechanism provides a new avenue for developing anticancer therapies.
  • This study challenges the exclusive focus on small molecules in LDH5 drug discovery programs.

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