Peptide-based LDH5 inhibitors enter cancer cells and impair proliferation

Abstract
Lactate dehydrogenase 5 (LDH5) is overexpressed in many cancers and is a potential target for anticancer therapy due to its\r\nrole in aerobic glycolysis. Small-molecule drugs have been developed as competitive inhibitors to bind substrate/cofactor\r\nsites of LDH5, but none reached the clinic to date. Recently, we designed the first LDH5 non-competitive inhibitor, cGmC9, a\r\npeptide that inhibits protein–protein interactions required for LDH5 enzymatic activity. Peptides are gaining a large interest as\r\nanticancer agents to modulate intracellular protein–protein interactions not targetable by small molecules; however, delivery\r\nof these peptides to the cytosol, where LDH5 and other anticancer targets are located, remains a challenge for this class of\r\ntherapeutics. In this study, we focused on the cellular internalisation of cGmC9 to achieve LDH5 inhibition in the cytosol. We\r\ndesigned cGmC9 analogues and compared them for LDH5 inhibition, cellular uptake, toxicity, and antiproliferation against\r\na panel of cancer cell lines. The lead analogue, [R/r]cGmC9, specifically impairs proliferation of cancer cell lines with high\r\nglycolytic profiles. Proteomics analysis showed expected metabolic changes in response to decreased glycolysis. This is the\r\nfirst report of a peptide-based LDH5 inhibitor able to modulate cancer metabolism and kill cancer cells that are glycolytic.\r\nThe current study demonstrates the potential of using peptides as inhibitors of intracellular protein–protein interactions\r\nrelevant for cancer pathways and shows that active peptides can be rationally designed to improve their cell permeation.

Author
Hadi H. Mohammad

DOI
https://doi.org/10.1007/s00018-022-04633-3

Publisher
Cellular and Molecular Life Sciences

ISSN
1420-9071

Publish Date: