Interrogating the Lactate Dehydrogenase Tetramerization Site Using (Stapled) Peptides
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
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| Enthalten in: |
Journal of medicinal chemistry - 63(2020), 9 vom: 14. Mai, Seite 4628-4643 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Thabault, Léopold [VerfasserIn] |
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| Links: |
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| Themen: |
Antineoplastic Agents |
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| Anmerkungen: |
Date Completed 02.11.2020 Date Revised 02.11.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.9b01955 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308355016 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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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| 700 | 1 | |a Brustenga, Chiara |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez Gache, Santiago A |e verfasserin |4 aut | |
| 700 | 1 | |a Prévost, Julien R C |e verfasserin |4 aut | |
| 700 | 1 | |a Kozlova, Arina |e verfasserin |4 aut | |
| 700 | 1 | |a Spillier, Quentin |e verfasserin |4 aut | |
| 700 | 1 | |a Liberelle, Maxime |e verfasserin |4 aut | |
| 700 | 1 | |a Benyahia, Zohra |e verfasserin |4 aut | |
| 700 | 1 | |a Messens, Joris |e verfasserin |4 aut | |
| 700 | 1 | |a Copetti, Tamara |e verfasserin |4 aut | |
| 700 | 1 | |a Sonveaux, Pierre |e verfasserin |4 aut | |
| 700 | 1 | |a Frédérick, Raphaël |e verfasserin |4 aut | |
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