Our lab aims to identify highly selective chemical reactions for the synthesis and modification of functional peptides and proteins. 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, 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), phosphonothiolates and phosphinates. We applied these reactions in a so-called P5-labeling protocol for the generation of new antibody-drug conjugates (ADCs) and for the development of cell-permeable proteins. 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.
 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.
 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.
 M.-A. Kasper et al., Angew. Chem. Int. Ed. 2019, 58, 11631-11636. 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.
 A.L. Baumann et al., J. Am. Chem. Soc. 2020, 142(20), 9544-9552.
 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.
 A.F.L. Schneider et al., Nature Chem. 2021, 13, 530-539.