Authors: Punt, Philip
Title: Rational design of metal-mediated DNA G-quadruplexes as DNAzymes
Language (ISO): en
Abstract: Apart from the widely known duplex structure DNA can fold into various secondary structures such as hairpin loops, triplexes and G-quadruplexes. The latter self-assemble from guanine rich strands by Hoogsteen base pairing to form stacked guanine tetrads. Since their discovery, G-quadruplexes became increasingly interesting in the field of chemical biology due to their property to control the elongation of telomeres and the expression of oncogenes. Furthermore, first examples of a DNAzyme activity in G quadruplexes were shown. Drawback of those systems was that the exact position and coordination environment of the catalytic active transition metal ion was largely unknown. In this context, the incorporation of covalently bound ligands into the backbone of G-quadruplex structures would be a next step in the development of DNAzymes. Recently, our group reported a first example of this strategy by incorporation of pyridine ligands, allowing the Cu(II) and Ni(II) mediated folding of G-quadruplex structures. This was then exploited to trigger the folding of a thrombin inhibiting aptamer upon Cu(II) addition. Now, we incorporated – inspired by the natural amino acid histidine – an imidazole-based ligand into G-quadruplex structures. We were able to show a tremendous acceleration of G-quadruplex formation as well as a stabilization by addition of different transition metals such as Cu(II), Ni(II) and Zn(II). By varying the number of incorporated imidazole units, we were able to finetune metal affinities in accordance with their preferred coordination number. The concept of metal mediated GQs was then expanded to design an active peroxidase with the cofactor Hemin which is activated by Cu(II) addition. Further the concept could be exploited for the design of sequences, that offer unsaturated coordination environments for Cu(II). These sequences could then be used for the enantioselective catalysis of Michael-Additions.
Subject Headings: G-quadruplex
DNA
DNAzyme
Subject Headings (RSWK): DNA
URI: http://hdl.handle.net/2003/40005
http://dx.doi.org/10.17877/DE290R-21888
Issue Date: 2020
Appears in Collections:Lehrstühle für Anorganische Chemie

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