title: A multivalent peptide as an activator of hypoxia inducible factor-1α.
abstract: Hypoxia inducible factor-1α (HIF-1α) is a transcription factor found in mammalian cells under hypoxia. While HIF-1α in hypoxia translocates to the nucleus where it transcribes the target genes including vascular endothelial growth factor (VEGF) mRNA, HIF-1α is degraded under normoxia, which involves its proline hydroxylation and subsequent binding to the von Hippel-Lindau protein-Elongin B-Elogin C (VBC) complex. Previously, peptide inhibitors against this interaction between hydroxylated HIF-1α and VBC have been developed to stabilize the transcriptional activity of HIF-1α by preventing the degradation of the protein even under normoxia. Despite the specific inhibition by these peptides, their poor inhibition potency needs to be improved for further clinical application. In this work, we have designed and prepared a streptavidin-based multivalent peptide inhibitor against the HIF-1α-VBC complexation. We have evaluated the potency of the multivalent peptide in terms of stabilization of HIF-1α and the downstream effect. As the result, we have found that the inhibitor showed about 13-fold lowered IC50 value compared with that of the corresponding monovalent peptide, thereby activating HIF-1α and leading to up-regulation of VEGF protein at the cellular level.
authors: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors: Hyuk Sung
authors: HS
authors: Kwon
authors: Jiae
authors: J
authors: Park
authors: Yong Keun
authors: YK
authors: Park
authors: Dae-Ro
authors: DR
authors: Ahn
mesh_terms: D000595:Amino Acid Sequence; D001710:Biotin / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D019809:Streptavidin / Q000737:chemistry / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010455:Peptides; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D001710:Biotin; D019809:Streptavidin