ChemBioChem research article on defined protein conjugates
Marc-André Kasper, Marcus Gerlach, Anselm F.L. Schneider, Christtiane Groneberg, Philipp Ochtrop, Stefanie Boldt, Dominik Schumacher, Jonas Helma, Heinrich Leonhardt, Mathias Christmann and Christian P.R. Hackenberger (in press) NHS-modified ethynylphosphonamidates enable the synthesis of configurationally defined protein conjugates. ChemBioChem 10.1002/cbic.201900587
Abstract cited from the publication:
"We describe the application of N-hydroxysuccinimide-(NHS-)-modified phosphonamidate building blocks for
the incorporation of Cysteine-selective ethynylphosphonamidates to lysine residues of proteins followed by thiol addition with small molecules and proteins. We demonstrate that our building blocks significantly lower undesired homo-crosslinking side-products that can occur with commonly applied succinimidyl 4-(Nmaleimidomethyl)
cyclohexane-1-carboxylate (SMCC) under physiological pH. The previously demonstrated stability of the
phosphonamidate moiety additionally solves the problem of premature maleimide hydrolysis, which can hamper the efficiency of the subsequent thiol addition. Furthermore, we developed a method to separate the phosphonamidate enantiomers to be able to synthesize protein-conjugates in a defined configuration. Finally, we apply our building blocks to the construction of functional Antibody Drug Conjugates (ADCs), analogously to the FDA-approved, SMCClinked
Kadcyla and to the synthesis of a functional antibody-protein conjugate."
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See also the main paper: Kasper MA, Stengl A, Ochtrop P, Gerlach M, Stoschek T, Schumacher D, Helma J, Penkert M, Krause E, Leonhardt H, Hackenberger CPR (2019) Ethynylphosphonamidates for the rapid and cysteine selective generation of efficacious Antibody-Drug-Conjugates. Angew. Chem. Int. Ed. Doi: 10.1002/anie.201904193