The power of chemoselectivity: Functional protein-conjugates for extra- and intracellular targeting

Seminar | November 20 | 11 a.m.-12 p.m. | 120 Latimer Hall

 Christian Hackenberger, Department of Chemistry, Humboldt University (Berlin)

 College of Chemistry

Our lab aims to identify reactions for the synthesis and modification of peptides and proteins. We apply these to study functional consequences of naturally occurring posttranslational protein modifications (PTMs), in particular phosphorylated Lys- and Cystein-residues,1 as well as to generate novel protein-conjugates for pharmaceutical and medicinal applications.2
In this presentation l will focus on the chemical modification of functional proteins and antibodies as well as their cellular delivery. 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 as well as recently developed bioorthogonal reactions and enzymatic ligations, for instance the so-called Tub-tag labeling.4 This concept is finally applied to generate new antibody-drug conjugates, multivalent protein-scaffolds as well as cell-permeable nanobodies, i.e. small antigen binding proteins that remain active within the reductive milieu inside living cells, to interfere with intracellular targets.5
References
1. a) J. Bertran-Vicente, R.A. Serwa, M. Schümann, P. Schmieder, E. Krause, C.P.R. Hackenberger, J. Am Chem. Soc. 2014, 136(39), 13622-13628; b) J. Bertran-Vicente, M. Penkert, O. Nieto, M. Schümann, P. Schmieder, E. Krause, C.P.R. Hackenberger, Nature Comm. 2016, 7,12703.
2. D. Schumacher, C.P.R. Hackenberger, Curr. Opin. Chem. Biol. 2014, 22, 62-69.
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(6), 1950-1953.
4. a) 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(46), 13787-13791, b) D. Schumacher, O. Lemke, J. Helma, L. Gerszonowicz, V. Waller, T. Stoschek, P.M. Durkin, N. Budisa, H. Leonhardt, B.G. Keller, C.P.R. Hackenberger, Chem. Sci. 2017, 8, 3471-3478
5. H. Herce, D. Schumacher, F.A. Mann, A. Ludwig, A. Schneider, M. Filies, S. Reinke, C. Cardoso, C.P.R. Hackenberger, Nature Chem. 2017, 9, 762-771; b) D. Schumacher, J. Helma, A.F.L. Schneider, H. Leonhardt, C.P.R. Hackenberger, Angew. Chem. Int. Ed. 2018, 57, 2314-2333..

 Light refreshments will be served at 10:50 at The Coffee Lab

 seminarcoordinator-cchem@berkeley.edu, 510-643-0572