electrospray tandem mass spectrometry; G-quadruplexes; oligonucleotides; antitumor drugs; double-stranded DNA; cisplatin; higher-order nucleic acids
Hari Yvonne, Nyakas Adrien, Stucki Silvan R., Schürch Stefan (2014), Elucidation of Nucleic Acid-Drug Interactions by Tandem Mass Spectrometry, in Chimia
, 68(3), 164-167.
Stucki Silvan R., Désiron Camille, Nyakas Adrien, Marti Simon, Leumann Christian J., Schürch Stefan (2013), Gas-phase Dissociation of homo-DNA Oligonucleotides, in J. Am. Soc. Mass Spectrom.
, 24(12), 1997-2006.
Nyakas Adrien, Blum Lorenz C., Stucki Silvan R., Reymond Jean-Louis, Schürch Stefan (2013), OMA and OPA - Software-Supported Mass Spectra Analysis of Native and Modified Nucleic Acids, in J. Am. Soc. Mass Spectrom.
, 24(2), 249-256.
This application aims at the investigation of the effects of adduct formation between organometallic anticancer drugs and higher-order nucleic acids, and the elucidation of fundamental aspects of nucleic acid dissociation in the gas-phase. Support is requested for one graduate student position for a period of three years. Feasibility of the two projects is demonstrated by preliminary results. Project A: Structural Investigation of Higher-Order Nucleic Acids and their Interaction with Organometallic Drugs:Higher-order nucleic acid structures play a key role in cellular processes. Thus, they represent a promising target for therapeutic applications. As a continuation of our ongoing research on quadruplex DNA-cisplatin adducts we propose to further investigate the interaction of organometallic anticancer agents (e.g. cisplatin and its younger generation derivatives) with higher-order nucleic acids. We propose to examine the stoichiometries, affinities, selectivities, and binding modes of different drugs to duplex and quadruplex structures by electrospray high-resolution tandem mass spectrometry, and to elucidate the underlying mechanistic aspects of the gas-phase dissociation of these assemblies. Special attention will be given to cross-linking of bi- and monomolecular quadruplexes, as these are of biological relevance. Project B: Fundamental Aspects of the Gas-phase Dissociation of Nucleic Acids - Highly Charged Oligonucleotides & Oligonucleotide Analogues:In a second sub-project of this grant application we propose to elucidate the fundamental mechanistic aspects of the dissociation of highly charged oligonucleotides, as these were found to undergo atypical fragmentation due to loss of cyanate from pyrimidine nucleobases and elimination of phosphoric acid, while simultaneously retaining the ribose moiety. Furthermore, proposed research aims at the elucidation of the gas-phase dissociation mechanism of modified oligonucleotides, which are of interest for antisense applications. Results will be a substantial contribution to the field, since deeper understanding of the fragmentation pathways of unnatural oligonucleotides is of utmost importance for tandem mass spectrometry to become a reliable analytical tool for structure and sequence elucidation in basic research and quality control.