News & Events

How Do You Write Chemo-selectivity? With a P, of Course!

Date: 
Friday, June 10, 2022 - 10:30 to 12:00
Speaker: 
Dr. Christian Hackenberger
Affiliation: 
Department of Chemical Biology, Forschungsinstitut für Molekulare Pharmakologie
Event Category: 
Special Seminar
Host: 
David Perrin
Location: 
Chemistry D215

Our lab aims to identify highly selective chemical reactions for the synthesis and modification of functional peptides and proteins.[1] We apply these so-called bioorthogonal reactions to study functional consequences of naturally occurring posttranslational protein modifications (PTMs), in particular phosphorylated Lys- and Cystein-peptides and proteins,[2] as well as to generate novel protein- and antibody-conjugates for pharmaceutical and medicinal applications.[1a,3]

In this presentation, l will focus on our most recent chemical development of Cys-selective P(V)-reagents including unsaturated phosphonamidates (see Scheme),[4] phosphonothiolates[5] and phosphinates.[6] We applied these reactions in a so-called P5-labeling protocol for the generation of new antibody-drug conjugates (ADCs)[3] and for the development of cell-permeable proteins.[7] With these next-generation drug conjugates, we show an improved efficacy compared to clinically approved cancer therapeutics on the market for the targeted delivery of pharmaceuticals.

References
[1] a) D. Schumacher, C.P.R. Hackenberger, Curr. Opin. Chem. Biol. 2014, 22, 62-69; b) P. Ochtrop, C.P.R. Hackenberger, Curr. Opin. Chem. Biol. 2020, 58, 28-36.

[2]    a) J. Bertran-Vicente et al., J. Am. Chem. Soc. 2014, 136(39), 13622-13628; b) J. Bertran-Vicente et al., Nature Comm. 2016, 7,12703; c) A. Hauser et al., Chem. Sci. 2020, 11, 12655-12661; d) A. Hauser et al., Chem. Eur. J. 2021, 27, 2326-2331.
[3]    M.-A. Kasper et al., Angew. Chem. Int. Ed. 2019, 58, 11631-11636.[4] a) M.-A. Kasper et al., Angew. Chem. Int. Ed. 2019, 58, 11625-11630; b) M.-A. Kasper et al., Chem Sci. 2019, 10, 6322-6329; c) Y. Park et al., Chem. Sci. 2021, 12, 8141-8148.

[5]    A.L. Baumann et al., J. Am. Chem. Soc. 2020, 142(20), 9544-9552.
[6]    a) C.E. Stieger et al., Angew. Chem. Int. Ed. 2021, 60, 15359-15364; C.E. Stieger et al., Angew. Chem. Int. Ed. 2022, in revision.
[7]    A.F.L. Schneider et al., Nature Chem. 2021, 13, 530-539.