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Study breakdown

Stapled Peptides That Disrupt Cancer-Fueling Enzyme LDH by Blocking Its Assembly

RPEP-051632020Thabault, Léopold; Brisson, Lucie; Brustenga, Chiara; Martinez Gache, Santiago A; Prévost, Julien R C; Kozlova, Arina; Spillier, Quentin; Liberelle, Maxime; Benyahia, Zohra; Messens, Joris; Copetti, Tamara; Sonveaux, Pierre; Frédérick, Raphaël
In VitroPreliminary evidence
The takeaway

A macrocyclic stapled peptide successfully disrupts LDH tetramerization, offering a new strategy for targeting this cancer metabolism enzyme.

New approach

First stapled peptides targeting LDH tetramerization rather than its catalytic site

What the researchers found

A macrocyclic stapled peptide binds the LDH tetramerization site and competes with the natural tetramerization domain, disrupting enzyme assembly.

Why it matters

LDH is an important cancer target but has resisted conventional drug design. Disrupting its assembly via stapled peptides opens a completely new therapeutic approach.

The numbers in context

Macrocyclic peptide disrupted LDH tetramers; validated by WaterLOGSY NMR and MST; dimeric model created

How the study worked

Computational dimer model design, WaterLOGSY NMR screening, microscale thermophoresis binding analysis, stapled peptide synthesis.

Who was studied

In vitro biophysical study

What this study cannot tell us

In vitro binding and competition data only. No cellular or in vivo efficacy demonstrated. Peptide cell permeability not assessed.

How to read the evidence

In vitro proof-of-concept with biophysical validation. Very early stage.

When this study was published

Published in 2020. Stapled peptide drug design continues to advance.

The bigger picture

This allosteric approach — disrupting protein quaternary structure rather than blocking the active site — could be applied to other tetrameric enzymes in cancer metabolism.

Questions still open

  • Does disrupting LDH tetramerization inhibit cancer cell metabolism?
  • Can the stapled peptide enter cancer cells effectively?
  • Would this approach work against specific LDH isoforms?

Common questions

What is LDH and why target it in cancer?
Lactate dehydrogenase converts pyruvate to lactate, a process cancer cells rely on heavily even when oxygen is available (the Warburg effect). Blocking LDH could starve cancer cells of this metabolic advantage.
What are stapled peptides?
Stapled peptides have a chemical bridge (staple) that locks them into a helical shape, making them more stable and resistant to degradation. This study used stapling to create a peptide that fits into the groove where LDH subunits normally join together.

Read the original research

Interrogating the Lactate Dehydrogenase Tetramerization Site Using (Stapled) Peptides.

Journal of medicinal chemistry, 63(9), 4628-4643

View on PubMed ↗Publisher’s paper ↗

Citation

Thabault, Léopold; Brisson, Lucie; Brustenga, Chiara; Martinez Gache, Santiago A; Prévost, Julien R C; Kozlova, Arina; Spillier, Quentin; Liberelle, Maxime; Benyahia, Zohra; Messens, Joris; Copetti, Tamara; Sonveaux, Pierre; Frédérick, Raphaël. (2020). Interrogating the Lactate Dehydrogenase Tetramerization Site Using (Stapled) Peptides.. Journal of medicinal chemistry, 63(9), 4628-4643. https://doi.org/10.1021/acs.jmedchem.9b01955