Orientation preferences of hairpin pyrrole–imidazole polyamides toward mCGG site
| Autor: | Toshikazu Bando, Shinsuke Sato, Sefan Asamitsu, Hiroshi Sugiyama |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
010405 organic chemistry
Chemistry Stereochemistry Organic Chemistry Clinical Biochemistry Pharmaceutical Science Sequence (biology) Orientation (graph theory) 01 natural sciences Biochemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound Drug Discovery Polyamide Molecular Medicine Molecule Imidazole Molecular Biology DNA Minor groove Pyrrole |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:2167-2171 |
| ISSN: | 0968-0896 |
| Popis: | Hairpin pyrrole–imidazole (Py-Im) polyamides are promising medium-sized molecules that bind sequence-specifically to the minor groove of B-form DNA. Here, we synthesized a series of hairpin Py-Im polyamides and explored their binding affinities and orientation preferences to methylated DNA with the mCGG target sequence. Thermal denaturation assays revealed that the five hairpin Py-Im polyamides, which were anticipated to recognize mCGG in a forward orientation, bind to nontarget DNA, GGmC, in a reverse orientation. Therefore, we designed five Py-Im polyamides that could recognize mCGG in a reverse orientation. We found that the two Py-Im polyamides containing Im/β pairs preferentially bound to mCGG in a reverse orientation. The reverse binding Py-Im polyamide successfully inhibited TET1 binding on the methylated DNA. Taken together, this study illustrated the importance of designing reverse binding Py-Im polyamides for the target sequence, mCGG, which paved the way for Py-Im polyamides that can be used with otherwise difficult to access DNA with CG sequences. |
| Databáze: | OpenAIRE |
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