The development of cyclic peptide inhibitors of hypoxia-inducible factors

Abstract

Hypoxia inducible factors (HIFs) are transcription factors that act as the master regulators of oxygen homeostasis. Diseases such as cancer can disrupt this homeostasis leading to areas with low environmental oxygen (hypoxia) especially in tumour cores. HIFs control the expression of hundreds of genes involved in processes such as metabolism, erythrogenesis, angiogenesis and pH regulation, all of which aid in the adaptation of cells to survive in hypoxic conditions. In the case of cancer this adaptation promotes the progression and metastasis of the disease, leading to HIF becoming a prominent target for therapeutic intervention. In this work, the structure activity relationship of the cyclic peptide HIF inhibitor cyclo-CLLFVY has been explored. A series of derivatives were synthesised via the incorporation of unnatural amino acids, which led to the development of a new lead peptide that was shown to bind to HIF with a 30-fold greater affinity than cyclo-CLLFVY. The improved peptide leads have been used in the development of several new in vitro assays for the quantification of HIF binding and inhibition of HIF activity. Determination of the structural basis of cyclo-CLLFVY binding was also attempted via an x-ray crystallographic approach, which led to the development of a novel HIF structure.

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

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