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Novel inhibitors target proteins for degradation

Modulating cellular function by interfering with the human proteome is a rapidly growing field. European researchers succeeded in controlling the level of cellular proteins through molecules that facilitate protein degradation.
Novel inhibitors target proteins for degradation
Under physiological conditions, cells constantly synthesise and destroy proteins, a phenomenon known as homeostasis. The most common degradation pathway for proteins is the ubiquitin-proteasome system, which recognises ubiquitin tags on proteins and guides them to the proteasome for hydrolysis.

Central to this process is an E3 ubiquitin ligase that recognises the substrate protein and recruits an ubiquitin-conjugating enzyme loaded with ubiquitin. As a result, ubiquitin ligases are emerging as more attractive targets for therapeutic intervention than current proteasome inhibitors.

The EU-funded ORTHOPROTACS (Design of orthogonal molecular probes targeting engineered von-Hippel Lindau (VHL) E3 ubiquitin ligase for the control of intracellular protein levels) project focused on the von Hippel-Lindau (VHL) E3 ubiquitin ligase. This ligase has important biological relevance as it targets the hypoxia inducible factor 1α (HIF-1α). HIF-1α is a transcription factor that regulates over 2 % of human genes, particularly those related to oxygen sensing and the hypoxic response.

The development of small molecule inhibitors against VHL E3 ligase would mimic the physiological response to low oxygen levels by increasing the expression of genes involved with the hypoxic response. Researchers designed and synthesised the next-generation of small molecule inhibitors of VHL, with binding affinities in the nanomolar range and improved lipophilicity.

X-ray crystallography studies revealed the interactions with HIF-1α and elucidated the determinants for improving binding affinity. Furthermore, researchers demonstrated that these molecules are cell permeable and induce a dose-dependent stabilisation of HIF-1α.

Overall, these inhibitors could help to elucidate the roles of both VHL and HIF in physiological and pathophysiological conditions. Most importantly, they will drive drug development efforts towards targeting the VHL-HIF-1α protein-protein interaction.

Related information


Inhibitor, protein, degradation, E3 ubiquitin ligase, VHL, HIF-1α
Record Number: 181163 / Last updated on: 2016-05-10
Domain: Biology, Medicine