Premium
Chemo‐Genetic Optimization of DNA Recognition by Metallodrugs using a Presenter‐Protein Strategy
Author(s) -
Zimbron Jeremy M.,
Sardo Alessia,
Heinisch Tillmann,
Wohlschlager Therese,
Gradinaru Julieta,
Massa Claudia,
Schirmer Tilman,
Creus Marc,
Ward Thomas R.
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201001573
Subject(s) - biotinylation , streptavidin , dna , chemistry , avidin , computational biology , nanotechnology , microbiology and biotechnology , biotin , biochemistry , biology , materials science
The mode of action of precious metal anticancer metallodrugs is generally believed to involve DNA as a target. However, the poor specificity of such drugs often requires high doses and leads to undesirable side‐effects. With the aim of improving the specificity of a ruthenium piano‐stool complex towards DNA, we employed a presenter protein strategy based on the biotin–avidin technology. Guided by the X‐ray structure of the assembly of streptavidin and a biotinylated piano‐stool, we explored the formation of metallodrug‐mediated ternary complexes with the presenter protein and DNA. The assemblies bound more strongly to telomere G‐quadruplexes than to double‐stranded DNA; chemo‐genetic modifications (varying the complex or mutating the protein) modulated binding to these targets. We suggest that rational targeting of small molecules by presenter proteins could be exploited to bind metallodrugs to preferred macromolecular targets.