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

Author information

Affiliations

  • 1. Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium.
      Authors
    • Thabault L 1, 2
    • Brustenga C 1
    • Prévost JRC 1
    • Kozlova A 1
    • Spillier Q 1, 2
    • Liberelle M 1
    • Frédérick R 1
    (7 authors)
  • 2. Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium.
      Authors
    • Thabault L 1, 2
    • Brisson L 2
    • Spillier Q 1, 2
    • Benyahia Z 2
    • Copetti T 2
    • Sonveaux P 2
    (6 authors)
  • 3. VIB-VUB Center for Structural Biology, B-1050 Brussels, Belgium.
      Authors
    • Martinez Gache SA 3
    • Messens J 3
    (2 authors)

ORCIDs linked to this article

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Journal of Medicinal Chemistry, 15 Apr 2020, 63(9):4628-4643
https://doi.org/10.1021/acs.jmedchem.9b01955 PMID: 32250117 

Abstract 

Lactate dehydrogenases (LDHs) are tetrameric enzymes of major significance in cancer metabolism as well as promising targets for cancer therapy. However, their wide and polar catalytic sites make them a challenging target for orthosteric inhibition. In this work, we conceived to target LDH tetramerization sites with the ambition of disrupting their oligomeric state. To do so, we designed a protein model of a dimeric LDH-H. We exploited this model through WaterLOGSY nuclear magnetic resonance and microscale thermophoresis for the identification and characterization of a set of α-helical peptides and stapled derivatives that specifically targeted the LDH tetramerization sites. This strategy resulted in the design of a macrocyclic peptide that competes with the LDH tetramerization domain, thus disrupting and destabilizing LDH tetramers. These peptides and macrocycles, along with the dimeric model of LDH-H, constitute promising pharmacological tools for the de novo design and identification of LDH tetramerization disruptors. Overall, our study demonstrates that disrupting LDH oligomerization state by targeting their tetramerization sites is achievable and paves the way toward LDH inhibition through this novel molecular mechanism.

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Read article at publisher's site: https://doi.org/10.1021/acs.jmedchem.9b01955

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Funding 

Funders who supported this work.

Belgian Federal Science Policy Office (1)

European Research Council (1)

F?d?ration Wallonie-Bruxelles (1)

  • Grant ID: ARC 14/19-058

    0 publications

Fonds De La Recherche Scientifique - FNRS (3)

Stichting Tegen Kanker (1)

T?l?vie (4)

  • Grant ID: 7.4548.13

    0 publications

  • Grant ID: 7.4611.11

    0 publications

  • Grant ID: 7.8504.18

    0 publications

  • Grant ID: 7.4507.14

    0 publications