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Literature DB >> 20041650

Inhibition of hypoxia inducible factor 1-transcription coactivator interaction by a hydrogen bond surrogate alpha-helix.

Laura K Henchey¹, Swati Kushal, Ramin Dubey, Ross N Chapman, Bogdan Z Olenyuk, Paramjit S Arora.

Abstract

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.

Entities: CellLine Chemical Disease Gene

Mesh：

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Year: 2010 PMID： 20041650 PMCID： PMC2810346 DOI： 10.1021/ja9082864

Source DB: PubMed Journal: J Am Chem Soc ISSN： 0002-7863 Impact factor: 15.419

28 in total

1. Enhanced metabolic stability and protein-binding properties of artificial alpha helices derived from a hydrogen-bond surrogate: application to Bcl-xL.

Authors: Deyun Wang; Wei Liao; Paramjit S Arora
Journal: Angew Chem Int Ed Engl Date: 2005-10-14 Impact factor: 15.336

2. A potent transactivation domain mimic with activity in living cells.

Authors: Bo Liu; Prasanna G Alluri; Peng Yu; Thomas Kodadek
Journal: J Am Chem Soc Date: 2005-06-15 Impact factor: 15.419

3. Optimized synthesis of hydrogen-bond surrogate helices: surprising effects of microwave heating on the activity of Grubbs catalysts.

Authors: Ross N Chapman; Paramjit S Arora
Journal: Org Lett Date: 2006-12-07 Impact factor: 6.005

Inhibition of hypoxia inducible factor 1-transcription coactivator interaction by a hydrogen bond surrogate alpha-helix.

1. Enhanced metabolic stability and protein-binding properties of artificial alpha helices derived from a hydrogen-bond surrogate: application to Bcl-xL.

2. A potent transactivation domain mimic with activity in living cells.

3. Optimized synthesis of hydrogen-bond surrogate helices: surprising effects of microwave heating on the activity of Grubbs catalysts.

4. Helix mimetics as inhibitors of the interaction of the estrogen receptor with coactivator peptides.

5. Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide.

6. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

7. Assessment of helical interfaces in protein-protein interactions.

8. Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response.

Review 9. Regulation of angiogenesis by hypoxia-inducible factor 1.

10. Amphipathic small molecules mimic the binding mode and function of endogenous transcription factors.

1. Design, synthesis and protein-targeting properties of thioether-linked hydrogen bond surrogate helices.

Review 2. Targeting recognition surfaces on natural proteins with peptidic foldamers.

3. Solid-phase synthesis of short α-helices stabilized by the hydrogen bond surrogate approach.

4. Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein.

Review 5. Advances in targeting 'undruggable' transcription factors with small molecules.

6. Synergistic enhancement of the potency and selectivity of small molecule transcriptional inhibitors.

Review 7. Inhibition of α-helix-mediated protein-protein interactions using designed molecules.

Review 8. Protein Domain Mimics as Modulators of Protein-Protein Interactions.

9. Positional effects of click cyclization on β-hairpin structure, stability, and function.

10. Structural basis for cyclic Py-Im polyamide allosteric inhibition of nuclear receptor binding.