Chemo-genetic optimization of DNA recognition by metallodrugs using a presenter-protein strategy.
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.
Zimbron
Jeremy M
JM
University of Basel, Department of Chemistry, Spitalstrasse 51, 4056 Basel, Switzerland.
Sardo
Alessia
A
Heinisch
Tillmann
T
Wohlschlager
Therese
T
Gradinaru
Julieta
J
Massa
Claudia
C
Schirmer
Tilman
T
Creus
Marc
M
Ward
Thomas R
TR
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D054856:G-Quadruplexes / Q000187:drug effects; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry; D019809:Streptavidin / Q000737:chemistry
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011506:Proteins; D012428:Ruthenium; D004247:DNA; D019809:Streptavidin