Stapled Peptides That Disrupt Cancer-Fueling Enzyme LDH by Blocking Its Assembly
A macrocyclic stapled peptide successfully disrupts LDH tetramerization, offering a new strategy for targeting this cancer metabolism enzyme.
Quick Facts
What This Study Found
A macrocyclic stapled peptide binds the LDH tetramerization site and competes with the natural tetramerization domain, disrupting enzyme assembly.
Key Numbers
Macrocyclic peptide disrupted LDH tetramers; validated by WaterLOGSY NMR and MST; dimeric model created
How They Did This
Computational dimer model design, WaterLOGSY NMR screening, microscale thermophoresis binding analysis, stapled peptide synthesis.
Why This Research 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 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.
What This Study Doesn't Tell Us
In vitro binding and competition data only. No cellular or in vivo efficacy demonstrated. Peptide cell permeability not assessed.
Questions This Raises
- ?Does disrupting LDH tetramerization inhibit cancer cell metabolism?
- ?Can the stapled peptide enter cancer cells effectively?
- ?Would this approach work against specific LDH isoforms?
Trust & Context
- Key Stat:
- New approach First stapled peptides targeting LDH tetramerization rather than its catalytic site
- Evidence Grade:
- In vitro proof-of-concept with biophysical validation. Very early stage.
- Study Age:
- Published in 2020. Stapled peptide drug design continues to advance.
- Original Title:
- Interrogating the Lactate Dehydrogenase Tetramerization Site Using (Stapled) Peptides.
- Published In:
- Journal of medicinal chemistry, 63(9), 4628-4643 (2020)
- Authors:
- 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
- Database ID:
- RPEP-05163
Evidence Hierarchy
Frequently Asked 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 More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-05163APA
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
MLA
Thabault, Léopold, et al. "Interrogating the Lactate Dehydrogenase Tetramerization Site Using (Stapled) Peptides.." Journal of medicinal chemistry, 2020. https://doi.org/10.1021/acs.jmedchem.9b01955
RethinkPeptides
RethinkPeptides Research Database. "Interrogating the Lactate Dehydrogenase Tetramerization Site..." RPEP-05163. Retrieved from https://rethinkpeptides.com/research/thabault-2020-interrogating-the-lactate-dehydrogenase
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.