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Mass Spectrometry for Mode-of-Action Studies of Metallodrug

Mass Spectrometry for Mode-of-Action Studies of Metallodrug

Monika Maria Cziferszky (ORCID: 0000-0002-3654-7812)
  • Grant DOI 10.55776/P37034
  • Funding program Principal Investigator Projects
  • Status ongoing
  • Start September 11, 2023
  • End September 10, 2027
  • Funding amount € 420,840
  • Project website
  • E-mail

Disciplines

Chemistry (66%); Medical-Theoretical Sciences, Pharmacy (34%)

Keywords

    Mass Spectrometry, Metallodrug, Mode-Of-Action

Abstract

Most approved drugs today are fairly small organic molecules, that exert their action through non-covalent binding, e.g., hydrogen bonding or ionic interactions, with a target structure in the human body similar to a key fitting into a lock. A considerably smaller number of drugs contain a metal atom and belong to the class of organometallic and coordination complexes, which consist of a single charged metal atom surrounded by a number of small molecules called ligands. A well-known example is the chemotherapeutic drug cisplatin, which is still in use today despite drawbacks and limitations on account of dose-limiting side-effects and development of resistances. The fundamental difference between an organic and a metallodrug is the ability of the later to form coordinative covalent, i.e. strong and long- lasting, bonds with a range of molecules inside the human body, a property that is governed both by the central metal ion as well as the number and type of surrounding ligands. This feature can be used in a therapeutic sense but at the same time can lead to unwanted side reactions, hence, understanding and controlling the reactivity of metallodrugs inside the human body is the most important challenge in the field of medicinal inorganic chemistry. This project investigates the reactivity of some approved metallodrugs and metal complexes in a developmental stage differing in both the central metal ion as well as the type and number of surrounding ligands. The aim of the project is to develop new analytical methods to enable quick and easy screening of potential metallodrugs and get insight into their molecular modes-of-action. Mass spectrometry is particularly suited for this purpose, as it provides insight into the various reactions taking place between metal complexes and biomolecules. Even ions of low-abundant side products can be isolated and further investigated. We recently developed a mass spectrometry-based method (Chem. Eur. J., 2021, 27, 16401 16406) that provides insight into the stability of the adducts formed between metal complexes and biomolecules. Within this project, this method will be further established and used for a broad range of different compounds. A second approach based on chromatography will be developed in order to get insight into the selectivity of metallodrugs for certain biomolecules. Data generated by these new methodologies will feed back into the design of the next generation of metal-based drugs with better efficacy and improved toxicity profiles.

Research institution(s)
  • Universität Innsbruck - 100%
Project participants
  • Brigitte Kircher, Medizinische Universität Innsbruck , national collaboration partner
  • Hristo Varbanov, Universität Innsbruck , national collaboration partner
International project participants
  • Valeria Ugone, Consiglio Nazionale delle Ricerche - Italy
  • Christian Hartinger, University of Auckland - New Zealand
  • Olga Mazuryk, Jagiellonian University in Krakow - Poland

Research Output

  • 1 Citations
  • 2 Publications
Publications
  • 2024
    Title In defense of platinum: Amino acidic polydentate ligands as a shield against sulphur-donor nucleophilic attacks
    DOI 10.1016/j.ica.2024.122158
    Type Journal Article
    Author Cucchiaro A
    Journal Inorganica Chimica Acta
    Pages 122158
    Link Publication
  • 2024
    Title In-Depth Mass Spectrometry Study of Vanadium(IV) Complexes with Model Peptides
    DOI 10.1021/acs.inorgchem.4c02683
    Type Journal Article
    Author Ku¨Ssner K
    Journal Inorganic Chemistry
    Pages 17785-17796
    Link Publication

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