Disulfide-rich peptide

The focus of this project is the investigation of bioactive, cysteine-rich peptides and proteins which are able to form intra- or intermolecular crosslinks via disulfide bonds. These bonds usually lead to a stabilization of the peptide/protein structure and in this way contribute to the biological activity of the corresponding molecules. The investigation of disulfide-bridged peptides is of great interest for drug development and therapeutic strategies [1]. The major purpose of this project is to investigate the influence of disulfide bonds on folding, structure, and biological activity of disulfide-rich peptides and miniproteins, primarily derived from biological sources.

Click here for an overview of research in the Department of Pharmaceutical Biochemistry and Bioanalytics.

© Pharmaceutical Biochemistry and Bioanalytics

Conotoxins are highly bioactive and specific, yet very complex, disulfide-rich peptides which are investigated in our research group. The individual structure of a conotoxin is determined both by its amino acid sequence [2,3], and by its specific disulfide connectivity. We observed that peptides with identical sequence can occur as differentially folded disulfide isomers possessing different bioactivities [2]. Recently, we demonstrated that a variety of methods such as MS/MS and NMR have to be combined in order to identify individual disulfide isomers unambiguously [4,5]. The synthesis of conotoxins is an extremely challenging task and needs diverse methods to result in the correct disulfide connectivity [2,4,5]. Our research focuses on several representatives of the µ-conotoxin family which have three disulfide bonds [2-5]. In collaboration with research groups of the University of Jena (Prof. Dr. Stefan H. Heinemann) and of the University of Lübeck (Prof. Dr. Enrico Leipold) the bioactivity of these conotoxins and their analogs is measured by electrophysiological experiments on different voltage-gated ion channels [2,3].Moreover, our recent efforts in employing computational methods to complement and further enhance outcomes of experimental studies have proven to be fruitful. Conformational changes are studied by aid of molecular dynamic simulations which provide insights into the underlying folding mechanism of the disulfide-rich peptide in consideration. Novel approaches to conduct MD simulations with these peptides have shown the significance of individual disulfide bonds for maintaining the native-like bioactive conformation [6].

[1] Nelson, L., Nature 429 (2004) 798-799.
[2] Tietze, A.A., Tietze, D., Ohlenschläger, O., Leipold, E., Ullrich, F., Kühl, T., Mischo, A., Buntkowsky, G., Görlach, M., Heinemann, S.H., Imhof, D., Angew. Chem. Int. Ed. 51 (2012) 4058-4061.
[3] Heimer, P., Tietze, A.A., Böhm, M., Giernoth, R., Kuchenbuch, A., Stark, A., Leipold, E., Heinemann, S.H., Kandt, C., Imhof, D., ChemBioChem 15 (2014) 2754-2765.
[4] Heimer, P., Tietze, A.A., Bäuml, C.A., Resemann, A., Mayer, F.J., Suckau, D., Ohlenschläger, O., Tietze, D., Imhof, D., Anal. Chem. 90 (2018) 3321-3327.
[5] Heimer, P., Schmitz, T., Bäuml, C.A., Imhof, D., J. Vis. Exp. 140 (2018) doi: 10.3791/58368.[6] Paul George, A.A., Heimer, P., Maaß, A., Hamaekers, J., Hofmann-Apitius, M., Biswas, A., Imhof, D.,  ACS Omega 3 (2018) 12330-12340.
Wird geladen