Project

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Probing the interactions of organometallic compounds with nucleic acids by tandem mass spectrometry

Applicant Schürch Stefan
Number 140628
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.04.2012 - 28.02.2013
Approved amount 64'206.00
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Keywords (7)

electrospray tandem mass spectrometry; G-quadruplexes; oligonucleotides; antitumor drugs; double-stranded DNA; cisplatin; higher-order nucleic acids

Lay Summary (English)

Lead
Lay summary

Aim of the project:  The project focuses on the investigation of higher-order nucleic acid structures and their interaction with organometallic anticancer drugs. Since such structures play a key role in cellular processes, they represent a highly promising target for chemotherapeutic applications that aim at blocking the expression of tumor promoting genes or at inducing programmed cell death (apoptosis) of malignous cancer cells. The interaction of duplex- and quadruplex DNA with cisplatin and related platinum compounds is studied by tandem mass spectrometric techniques. Once the fundamental behavior of the oligonucleotide-drug adducts in the mass spectrometer (preferences and mechanisms of gas-phase dissociation) has been elucidated, the technique will be applied to the identification of the binding motifs of the drugs and the localization of the binding sites.

Significance of the project: With the proposed research, we aim at a deeper understanding of the binding of organometallic anticancer agents to higher-order nucleic acids in order to extend our knowledge about their biological functions and to asses their potential as targets in anticancer therapy. Significant impact on biomedical research, especially on therapeutic strategies, can be foreseen, once reliable and accurate analytical protocols for probing such complex systems have been established. 


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Elucidation of Nucleic Acid-Drug Interactions by Tandem Mass Spectrometry
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.
Gas-phase Dissociation of homo-DNA Oligonucleotides
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.
OMA and OPA - Software-Supported Mass Spectra Analysis of Native and Modified Nucleic Acids
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.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the Swiss Group for Mass Spectrometry Talk given at a conference Sequencing of Sugar-modified Nucleic Acid Analogues by Tandem Mass Spectrometry 01.11.2012 Beatenberg, Switzerland Stucki Silvan;
Annual Meeting of the Swiss Chemical Society Poster OMA & OPA - Software Tool for Mass Spectra Analysis of Natural and Modified Nucleic Acids 13.09.2012 Zürich, Switzerland Stucki Silvan; Schürch Stefan;
Annual Meeting of the Swiss Chemical Society Poster Sequencing of Sugar-Modified Nucleic Acid Analogues by Tandem Mass Spectrometry 13.09.2012 Zürich, Switzerland Schürch Stefan; Stucki Silvan;
60th ASMS Conference on Mass Spectrometry and Allied Topics Poster Tandem Mass Spectrometric Analysis of Sugar-Modified Nucleic Acid Analogues 20.05.2012 Vancouver, Canada Stucki Silvan; Schürch Stefan;


Awards

Title Year
SGMS Meeting Student Award, Best Oral Presentation 2012

Associated projects

Number Title Start Funding scheme
149892 Investigation of the interaction of transition metal based anticancer drugs with higher-order nucleic acids 01.03.2014 Project funding (Div. I-III)
121843 Binding of metal ions and organometallic compounds to oligonucleotides explored by mass spectrometry 01.03.2009 Project funding (Div. I-III)

Abstract

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.
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