Inhibition of hypoxia inducible factor 1-transcription coactivator interaction by a hydrogen bond surrogate alpha-helix.
Designed ligands that inhibit hypoxia-inducible gene expression could offer new tools for genomic research and, potentially, drug discovery efforts for the treatment of neovascularization in cancers. We report a stabilized alpha-helix designed to target the binding interface between the C-terminal transactivation domain (C-TAD) of hypoxia-inducible factor 1alpha (HIF-1alpha) and cysteine-histidine rich region (CH1) of transcriptional coactivator CBP/p300. The synthetic helix disrupts the structure and function of this complex, resulting in a rapid downregulation of two hypoxia-inducible genes (VEGF and GLUT1) in cell culture.
Henchey
Laura K
LK
Department of Chemistry, New York University, New York, New York 10003, USA.
Kushal
Swati
S
Dubey
Ramin
R
Chapman
Ross N
RN
Olenyuk
Bogdan Z
BZ
Arora
Paramjit S
PS
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004220:Disulfides / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006860:Hydrogen Bonding; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D026121:Indole Alkaloids / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D004220:Disulfides; D051793:Hypoxia-Inducible Factor 1; D026121:Indole Alkaloids; D015534:Trans-Activators; C001598:chetomin