Designed β‑Hairpins Inhibit LDH5 Oligomerization and Enzymatic Activity

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 β-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 β-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.