Department of Chemistry
Professor Dr. Christian P. R. Hackenberger
Humboldt Universität zu Berlin
Leibniz-Institut für Molekulare Pharmakologie (FMP)
New chemoselective reactions for the site-specific posttranslational modification and cellular delivery of functional proteins
Place: Lilla hörsalen, KB3A9
Host: Christian Hedberg, Department of Chemistry
Our lab constantly aims to identify new bioorthogonal reactions for the synthesis and modification of functional peptides and proteins. We apply these highly selective organic reactions to study functional consequences of naturally occurring posttranslational protein modifications (PTMs) as well as to generate novel peptide- and protein-conjugates for pharmaceutical and medicinal applications.(1)
In the first part of this lecture, our recent efforts in the synthesis and analysis of naturally occurring labile PTMs including the synthesis of site-specifically phosphorylated Lys-peptides (pLys) using the Staudinger-phosphite reaction (2a) as well as phosphorylated Cys-peptides (pCys), (2b) will be presented.
In the second part of this presentation, I will focus on the cellular delivery of modified functional proteins. Thereby, we employ cyclic cell penetrating peptides (cCPPs) to transport a functional full length protein to the cytosol of living cells as recently demonstrated by the direct delivery of GFP-conjugates.(3) For protein modification we use a combined approach of intein expression, bioorthogonal reactions and recently developed enzymatic ligations, called Tub-tag labeling.4 This concept is finally applied to generate site-specifically labelled cell permeable nanobodies, i.e. small antigen binding proteins that remain active within the reductive milieu inside living cells, to interfere with intracellular targets.
(1.) D. Schumacher, C.P.R. Hackenberger, Curr. Opin. Chem. Biol. 2014, 22, 62-69.
(2.) a)J. Bertran-Vicente, R.A. Serwa, M. Schümann, P. Schmieder, E. Krause, C.P.R. Hackenberger, J. Am Chem. Soc. 2014, 136, 13622-13628;
(b) J. Bertran-Vicente, M. Penkert, O. Nieto, M. Schümann, P. Schmieder, E. Krause, C.P.R. Hackenberger, submitted.
(3.) N. Nischan, H.D. Herce, F. Natale, N. Bohlke, N. Budisa, M.C. Cardoso, C.P.R. Hackenberger, Angew. Chem. Int. Ed. 2015, 54, 1950-1953.
(4.) D. Schumacher, J. Helma, F.A. Mann, G. Pichler, F. Natale, E. Krause, M.C. Cardoso, C.P.R. Hackenberger, H. Leonhardt, Angew. Chem. Int. Ed. 2015, 54, 13787-13791.