Microreactor for electrochemical conversion in drug screening and proteomics

Floris Teunis Gerardus van den Brink

Research output: ThesisPhD Thesis - Research UT, graduation UTAcademic

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Abstract

Electrochemical conversions play an important role in processes relevant to industry and society, such as the electrolysis and treatment of water, the operation of fuel cells and batteries, and the production of fine chemicals. In this thesis, the focus is on two major applications in which electrochemistry is explored as an alternative approach to assays that normally make use of chemical or enzymatic reactions: those of drug screening and protein identification. The majority of marketed drugs are metabolized through oxidation by enzymes of the cytochrome P450 family, thereby producing phase I metabolites. For pharmaceutical companies it is essential to thoroughly screen candidate drugs for potentially toxic metabolites, in order to avoid high costs associated with their failure in late development stages. Generating phase I metabolites directly at an electrode in an electrochemical cell is a purely instrumental approach to metabolite analysis. Electrochemical cells can be coupled directly to analytical instrumentation such as liquid chromatography and mass spectrometry for rapid and sensitive detection. Using the same approach, the toxicity of phase I metabolites can be screened by allowing them to react with biomolecules such as proteins. Furthermore, other reactions in the biotransformation pathway can be mimicked, such as the generation of phase II metabolites and detoxification. Identification and characterization of proteins is important to understand processes related to disease development. Standard routines in protein analysis involve enzymatic digestion using proteases such as trypsin, followed by mass spectrometric analysis of the resulting proteolytic peptides. Electrochemical protein cleavage is emerging as an instrumental alternative that enables specific cleavage at tyrosine and tryptophan peptide bonds, without the need for sample purification due to the absence of cleavage reagents. Electrochemical cells designed for performing conversions in the often precious samples for proteomics and drug screening studies should be of low volume, efficient and either easy to clean or cheap and single-use.
Original languageEnglish
Awarding Institution
  • University of Twente
Supervisors/Advisors
  • Olthuis, Wouter , Advisor
  • van den Berg, Albert , Supervisor
  • Odijk, Mathieu , Advisor
Thesis sponsors
Award date17 Jun 2016
Place of PublicationEnschede
Publisher
Print ISBNs978-90-365-4145-9
DOIs
Publication statusPublished - 17 Jun 2016

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Metabolites
Screening
Electrochemical cells
Pharmaceutical Preparations
Proteins
Fuel cells
Detoxification
Peptides
Poisons
Liquid chromatography
Biomolecules
Electrochemistry
Electrolysis
Tryptophan
Trypsin
Cytochrome P-450 Enzyme System
Purification
Mass spectrometry
Toxicity
Tyrosine

Keywords

  • EWI-27089

Cite this

van den Brink, Floris Teunis Gerardus. / Microreactor for electrochemical conversion in drug screening and proteomics. Enschede : Gildeprint, Enschede, 2016. 195 p.
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Microreactor for electrochemical conversion in drug screening and proteomics. / van den Brink, Floris Teunis Gerardus.

Enschede : Gildeprint, Enschede, 2016. 195 p.

Research output: ThesisPhD Thesis - Research UT, graduation UTAcademic

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N2 - Electrochemical conversions play an important role in processes relevant to industry and society, such as the electrolysis and treatment of water, the operation of fuel cells and batteries, and the production of fine chemicals. In this thesis, the focus is on two major applications in which electrochemistry is explored as an alternative approach to assays that normally make use of chemical or enzymatic reactions: those of drug screening and protein identification. The majority of marketed drugs are metabolized through oxidation by enzymes of the cytochrome P450 family, thereby producing phase I metabolites. For pharmaceutical companies it is essential to thoroughly screen candidate drugs for potentially toxic metabolites, in order to avoid high costs associated with their failure in late development stages. Generating phase I metabolites directly at an electrode in an electrochemical cell is a purely instrumental approach to metabolite analysis. Electrochemical cells can be coupled directly to analytical instrumentation such as liquid chromatography and mass spectrometry for rapid and sensitive detection. Using the same approach, the toxicity of phase I metabolites can be screened by allowing them to react with biomolecules such as proteins. Furthermore, other reactions in the biotransformation pathway can be mimicked, such as the generation of phase II metabolites and detoxification. Identification and characterization of proteins is important to understand processes related to disease development. Standard routines in protein analysis involve enzymatic digestion using proteases such as trypsin, followed by mass spectrometric analysis of the resulting proteolytic peptides. Electrochemical protein cleavage is emerging as an instrumental alternative that enables specific cleavage at tyrosine and tryptophan peptide bonds, without the need for sample purification due to the absence of cleavage reagents. Electrochemical cells designed for performing conversions in the often precious samples for proteomics and drug screening studies should be of low volume, efficient and either easy to clean or cheap and single-use.

AB - Electrochemical conversions play an important role in processes relevant to industry and society, such as the electrolysis and treatment of water, the operation of fuel cells and batteries, and the production of fine chemicals. In this thesis, the focus is on two major applications in which electrochemistry is explored as an alternative approach to assays that normally make use of chemical or enzymatic reactions: those of drug screening and protein identification. The majority of marketed drugs are metabolized through oxidation by enzymes of the cytochrome P450 family, thereby producing phase I metabolites. For pharmaceutical companies it is essential to thoroughly screen candidate drugs for potentially toxic metabolites, in order to avoid high costs associated with their failure in late development stages. Generating phase I metabolites directly at an electrode in an electrochemical cell is a purely instrumental approach to metabolite analysis. Electrochemical cells can be coupled directly to analytical instrumentation such as liquid chromatography and mass spectrometry for rapid and sensitive detection. Using the same approach, the toxicity of phase I metabolites can be screened by allowing them to react with biomolecules such as proteins. Furthermore, other reactions in the biotransformation pathway can be mimicked, such as the generation of phase II metabolites and detoxification. Identification and characterization of proteins is important to understand processes related to disease development. Standard routines in protein analysis involve enzymatic digestion using proteases such as trypsin, followed by mass spectrometric analysis of the resulting proteolytic peptides. Electrochemical protein cleavage is emerging as an instrumental alternative that enables specific cleavage at tyrosine and tryptophan peptide bonds, without the need for sample purification due to the absence of cleavage reagents. Electrochemical cells designed for performing conversions in the often precious samples for proteomics and drug screening studies should be of low volume, efficient and either easy to clean or cheap and single-use.

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