Field of research
- Chemical synthesis of hydrophobic peptides and proteins (membrane proteins, ion channels)
- Structure-activity relationship studies of bioactive toxins
- Mechanistic studies of peptide/target interactions
- Influence of biomolecule surrounding on its structure and function
SYNTHESIS, PURIFICATION AND CHARACTERIZATION OF MEMBRANE PROTEINS
Membrane proteins comprise around 30% of the human genome and account for around 60% of pharmaceutical targets. They are the key drug targets because they are involved in essential processes in the cell, including the control of information and material flow between cells as well as the mediation and propagation of nerve impulses. The study of membrane proteins leads to new and improved pharmaceutical treatments for a wide range of illnesses such as migraine, multiple sclerosis, cancer together with muscle and immune system disorders.
Within this project we develop novel strategies for the synthesis of membrane proteins and hydrophobic peptides in order to facilitate their availability. We are interested in the determination of structural motifs of these transmembrane proteins and elucidation their interaction mode with potent drug leads.
STRUCTURAL INSIGHTS INTO THE MECHANISM OF ACTION OF NEUROTOXIC VOLTAGE SENSOR-TARGETING PEPTIDES
To date, most of the known drugs applied in therapy as local anaesthetics, antiepileptics and antiarythmics have been reported to exhibit little or no selectivity across the nine voltage-gated sodium channel (VGSC) subtypes, which could result in toxicity due to the binding to off-targets. The reason for that is their interaction with the pore-forming modules of the ion channel whose sequence is highly conserved between the channel subtypes with the same ion selectivity.
Our goal is the development of highly specific and selective pharmacologically active agents, which are able to modulate VGSCs in a state-dependent manner. We study such molecular constructs allowing for the recognition between the different VGSC subtypes.
- Tietze, D.#, Leipold, E.#, Heimer, P., Böhm, M., Winschel, W., Imhof, D., Heinemann, S.H., and Tietze, A.A.,* Molecular interaction of δ-conopeptide EVIA with voltage-gated Na+ channels, (2016), BBA General Subjects, accepted
CHEMICAL SYNTEHSIS OF PROTEIN NANOPORES ON THE BASIS OF ION CHANNELS AND HELIX-FORMING PEPTIDES
In living organisms, the transport of ions is performed by ion channels and transporters. To date the basic principles of working mechanisms and the reason for their efficiency/high selectivity are well understood. This information will help us to develop ion-selective pores for various technical applications in biophysical, biochemical and medical fields.
This subproject of the LOEWE project “iNAPO” focuses on the chemical synthesis of switchable (pH, Ion-type, ligand binding) protein-based nanopores mimicking biological ion channels and peptides forming helix structures. Solid-phase peptide synthesis of pore-forming membrane proteins are performed in our lab, applying our lab know-how of different methods for the synthesis of membrane proteins. Chemical modification of polymer support-facing amino acid side-chains are being made in order to anchor proteins and peptides to polymer-based scaffolds.
IONIC LIQUIDS AND THEIR INFLUENCE ON PETIDE CHEMISTRY AND STRUCTURE
The interest in ionic liquids (IL) has increased in recent years because of their unique properties such as low vapor pressure, low flammability, low toxicity, high stability and electric conductivity.
ILs are molten salts at room temperature and thus these liquids are composed entirely of ions. In comparison to classical salts with high melting points, ILs comprise dissymmetrical organic cations like the alkyl-pyridinium or dialkyl-imidazolium cation and organic/inorganic anions (chloride, acetate). By different combinations of cations and anions a large number of possible molten salts can be generated. As a result multiple alternative solvents for organic synthesis can be obtained.
ILs are used in several areas involving biological macromolecules, such as enzymatic catalysis, oxidative folding or native chemical ligation e.g. because of their structure-stabilizing capabilities.
This project focuses on the investigation of interactions of ionic liquids with biomolecules (i.e. cysteine-rich peptides) at the atomistic level. The global objective of this project is to develop protocols and optimal conditions for ionic liquid – supported reactions of biomolecules.