Book of Abstracts - Ruhr-Universität Bochum

OP-33
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Chemo-Genetic Optimization of DNA Recognition by Metallodrugs using a
Presenter Protein Strategy
Jeremy M. Zimbron, a A. Sardo, a T. Heinisch, a,b T. Wohlschlager, c J. Gradinaru, d C. Massa, b
T. Schirmer, *b Marc Creus, *a and Thomas R. Ward *a
aUniversity of Basel, Department of Chemistry, Spitalstrasse 51, Basel 4056, Switzerland, b University
of Basel, Biozentrum, Klingelbergstrasse 50/70, Basel 4056, Switzerland, c University of Neuchâtel,
Institute of Chemistry, Avenue de Bellevaux 51, Neuchâtel 2009, Switzerland
DNA is a privileged target of anticancer metallodrugs like cisplatin. However, such drugs often suffer
from high toxicity and drug-resistance due to non-selective binding to other than oncogenic DNA. 1
To increase selectivity of small molecule drugs for macromolecular targets, “surface borrowing” can
be used to provide additional surface contacts via a presenter protein, which modulates the specificity
and affinity of ligand–macromolecule interaction. 2 The use of bifunctional molecules based on biotinstreptavidin
technology has been used for targeting RNA, in which a contribution for protein contacts
to the anti-tobramycin RNA aptamer was suggested. 3 Inspired by these presenter protein strategies and
our previous experience of enantioselective artificial metalloenzymes, 4 we synthesized a biotinylated
metallodrug (compound 1, Fig.1) inspired on promising anticancer Ru(II) piano-stool complexes, 4 for
incorporation into streptavidin (Sav).
Here we shown that a supramolecular assembly of a drug with a presenter protein can modulate
selectivity through provision of additional non-covalent interactions with the target that are not
typically available to small molecule drugs, thus allowing selectivity toward macromolecules such as
DNA telomeres.
Fig.1 Presenter protein strategy for targeting telomeric DNA with ruthenium metallodrugs.
References
1. L. Kelland, Nat. Rev. Cancer 2007, 7, 573.
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1953.
3. I. Harvey, P. Garneau, J. Pelletier, Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 1882.
4. M. Creus, A. Pordea, T. Rossel, A. Sardo, C. Letondor, A. Ivanova, I. Letrong, R. E. Stenkamp, T.
R. Ward, Angew. Chem. Int. Ed. 2008, 47, 1400.
5. P. C. Bruijnincx, P. J. Sadler, Curr. Opin. Chem. Biol. 2008, 12, 197.
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