Interrogating the lactate dehydrogenase tetrameric interface using (stapled) peptides and short proteins : an original approach to protein inhibition
(2020)
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- Authors
Thabault, Léopold 
- Supervisors
- Abstract
- Lactate Dehydrogenases (LDHs) are tetrameric enzymes of major significance in cancer metabolism and promising cancer therapy targets. However, their wide and polar catalytic sites make them a challenging target for orthosteric inhibition. In this work, we conceived to target LDH tetrameric interface with the ambition of disrupting their oligomeric state. To do so, we designed a protein model of a dimeric LDH. We exploited this model using orthogonal biophysical techniques to identify and characterize two families of α-helical peptides and stapled derivatives that targeted the LDH tetrameric interface and destabilized the tetrameric protein. These (stapled) peptides, along with the dimeric model of LDH, constitute promising pharmacological tools for the de novo design and identification of LDH tetramerization disruptors. Overall, this work demonstrates that targeting the LDH interface is achievable and paves the way toward LDH inhibition through this novel molecular mechanism.
- Affiliations
Citations
Thabault, L. (2020). Interrogating the lactate dehydrogenase tetrameric interface using (stapled) peptides and short proteins : an original approach to protein inhibition. https://hdl.handle.net/2078.5/260603