HIF-1 alpha peptide derivatives with modifications at the hydroxyproline residue as activators of HIF-1 alpha

Abstract

Hypoxia-inducible factor (HIF)-1 alpha undergoes degradation under normoxia, which involves its proline hydroxylation and subsequent binding of proline-hydroxylated HIF-1 alpha to the von Hippel-Lindau protein-Elongin B-Elongin C (VBC) complex. In this study, we designed and synthesized a series of peptides containing 556-575 residues of HIF-1 alpha with modi. cations at the Pro-564 residue to inhibit the interaction between proline-hydroxylated HIF-1 alpha and VBC. Employing a fluorescence polarization-based interaction assay, we evaluated inhibitory potency of these peptides and selected potent inhibitors. We then analyzed their effects in the cell level to show that the selected inhibitors induced HIF-1 alpha stabilization in normoxic cells. Considering that proline hydroxylation of HIF-1 alpha is routinely targeted for modulating the HIF pathway, our approach of using inhibitors against the interactions between HIF-1 alpha and VBC would provide an alternative way of upregulating HIF-1 activity. (C) 2009 Elsevier Ltd. All rights reserved.