Peptide-based LDH5 inhibitors enter cancer cells and impair proliferation

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Lactate dehydrogenase 5 (LDH5) is overexpressed in various cancers, playing a crucial role in aerobic glycolysis.
• Existing small-molecule LDH5 inhibitors face challenges, with none currently approved for clinical use.
• Peptides offer a promising therapeutic strategy for targeting intracellular protein-protein interactions, but their cellular delivery remains a significant hurdle.

Purpose of the Study:

• To investigate the cellular internalization and efficacy of peptide-based inhibitors targeting LDH5.
• To design and optimize novel peptide analogues for improved LDH5 inhibition and cancer cell targeting.
• To evaluate the potential of peptide inhibitors in modulating cancer metabolism and proliferation.

Main Methods:

• Design and synthesis of cGmC9 peptide analogues.
• Assessment of LDH5 inhibition, cellular uptake, and cytotoxicity.
• Antiproliferation assays against a panel of cancer cell lines.
• Proteomics analysis to evaluate metabolic changes.

Main Results:

• The lead analogue, [R/r]cGmC9, demonstrated specific inhibition of cancer cell lines with high glycolytic profiles.
• Successful cellular internalization of the peptide analogue was achieved, leading to cytosolic LDH5 inhibition.
• Proteomics confirmed expected metabolic alterations consistent with reduced glycolysis.
• [R/r]cGmC9 effectively reduced cancer cell proliferation.

Conclusions:

• This study presents the first peptide-based LDH5 inhibitor capable of modulating cancer metabolism and selectively killing glycolytic cancer cells.
• The findings highlight the potential of rationally designed peptides as therapeutic agents targeting intracellular protein-protein interactions in cancer.
• The developed peptide analogues show promise for improving cell permeation and therapeutic efficacy in cancer treatment.