Towards a small molecule inhibitor of the HIF-1?/HIF-1? protein-protein interaction

Abstract

Hypoxia-inducible factor (HIF) is a heterodimeric, oxygen-dependent, transcription factor that regulates the cellular response to hypoxia by directing the expression of multiple genes, such as those involved in angiogenesis and glucose transport. HIF activation has been shown to aid the survival of cancer cells in hypoxic regions; hence it is viewed as a potentially important target for cancer therapy.
There are two predominant isoforms of HIF, HIF-1 and HIF-2, formed by heterodimerisation of HIF-1? or HIF-2?, respectively, with HIF-1?. The dimerisation of the two subunits is necessary for DNA-binding and subsequent activation of transcription. Miranda et al. (2013) have recently identified a six amino acid cyclic peptide inhibitor of HIF dimerisation (cyclo-CLLFVY); the Tat-tagged variant is called P1. This has shown activity within several cell-based assays.1
This project sought to identify which amino acid residues of cyclo-CLLFVY were critical to its activity by synthesising five alanine analogues and testing them in cell and biophysical assays. It was not possible to identify an active motif and it could be concluded that the specific conformation of the intact cyclic peptide is required for activity. The functionality of independently bacterially expressed fragments of HIF-1? and HIF-1? was also validated by an EMSA. The Tavassoli group used these proteins to establish the binding location of the inhibitor to the HIF-1?-PAS-B domain (work by A. Tavassoli and A. Male).

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Identifiers

ORCID for Ali Tavassoli: orcid.org/0000-0002-7420-5063

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