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Redesigned peptide-based LDH5 inhibitors enter cancer cells efficiently and impair proliferation

ABSTRACT: Lactate dehydrogenase 5 (LDH5), an enzyme overexpressed in many cancers, is an attractive target for anticancer therapy. Recently, we successfully designed an LDH5 peptide inhibitor, cGmC9, by targeting protein-protein interactions required for LDH5 enzymatic activity. LDH5 is expressed in the cytosol, therefore this peptide inhibitor has to enter cancer cells to hit its target. In this study we designed cGmC9 analogues and evaluated their internalisation, membrane toxicity, and antiproliferative activity against a panel of cancer cell lines with distinct metabolic profiles. Lead analogue [R/r]cGmC9 showed low toxicity and impaired proliferation in triple negative breast cancer cells, and proteomics analysis showed expected compensatory metabolic changes in response to LDH5 inhibition. These results confirm that LDH5 peptide inhibitors enter cancer cells, reach their cytosol, inhibit LDH5 activity and kill glycolytic tumour cells. Small-molecule drugs have been developed to target the substrate/cofactor sites of LDH5, but none has reached the clinic to date due to cross-reactivity associated with targeting NADH binding site, or low potency in vivo associated with poor stability and poor membrane permeability. This is the first study demonstrating ability of a designed peptide to inhibit LDH5 activity in cancer cells, and confirms the potential of using peptides as inhibitors of intracellular protein-protein interactions relevant for cancer pathways.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Andrew Lai

LAB HEAD: Carlos Salomon

PROVIDER: PXD029126 | Pride | 2025-05-06

REPOSITORIES: Pride

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Peptide-based LDH5 inhibitors enter cancer cells and impair proliferation.

Nadal-Bufí Ferran F Chan Lai Y LY Mohammad Hadi H HH Mason Jody M JM Salomon Carlos C Lai Andrew A Thompson Erik W EW Craik David J DJ Kaas Quentin Q Henriques Sónia T ST

Cellular and molecular life sciences : CMLS 20221127 12

Lactate dehydrogenase 5 (LDH5) is overexpressed in many cancers and is a potential target for anticancer therapy due to its role in aerobic glycolysis. Small-molecule drugs have been developed as competitive inhibitors to bind substrate/cofactor sites of LDH5, but none reached the clinic to date. Recently, we designed the first LDH5 non-competitive inhibitor, cGmC9, a peptide that inhibits protein-protein interactions required for LDH5 enzymatic activity. Peptides are gaining a large interest as ...[more]

PMID: 36436181

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