N‐Hydroxysuccinimide‐Modified Ethynylphosphonamidates Enable the Synthesis of Configurationally Defined Protein Conjugates,ChemBioChem

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N‐Hydroxysuccinimide‐Modified Ethynylphosphonamidates Enable the Synthesis of Configurationally Defined Protein Conjugates
ChemBioChem ( IF 2.6 ) Pub Date : 2019-12-30 , DOI: 10.1002/cbic.201900760
Marc‐André Kasper _{1,

2,

3} , Marcus Gerlach _{3,

4} , Anselm F. L. Schneider _{1,

5} , Christiane Groneberg ₅ , Philipp Ochtrop _{1,

3} , Stefanie Boldt _{3,

4} , Dominik Schumacher _{1,

2,

3,

4} , Jonas Helma _{3,

4} , Heinrich Leonhardt ₄ , Mathias Christmann ₅ , Christian P. R. Hackenberger _{1,

2}

Affiliation

NHS‐phosphonamidate‐superglue: Ethynylphosphonamidate building blocks carrying an NHS residue selectively connect antibody lysine residues with thiol‐containing drugs or proteins. Outstanding selectivity for cysteine under physiological conditions can reduce the homo‐crosslinking side products in the lysine‐modification step that can occur with alternative linker systems such as SMCC. The highly stable phosphonamidate–cysteine adduct “locks” a toxic payload to an antibody, thereby giving rise to a new generation of stably linked antibody–drug conjugates. In addition, enantiomerically pure building blocks enable the synthesis of protein conjugates with defined configuration. More information can be found in the full paper by M.‐A. Kasper, C. P. R. Hackenberger, et al. Image designed and created by Barth van Rossum.

中文翻译：

N-羟基琥珀酰亚胺修饰的乙炔基膦酰胺化物可合成结构定义的蛋白质缀合物

NHS-氨基磷酸酯-强力胶：带有NHS残基的乙炔基氨基磷酸酯构件将抗体赖氨酸残基与含硫醇的药物或蛋白质选择性连接。在生理条件下，半胱氨酸具有出色的选择性，可以减少赖氨酸修饰步骤中的同交联副产物，而这种副产物可能是由诸如SMCC之类的其他接头系统发生的。高度稳定的膦酰胺-半胱氨酸加合物“锁定”了抗体的有毒有效负载，从而产生了新一代的稳定连接的抗体-药物偶联物。另外，对映体纯的构建基块使得能够合成具有确定构型的蛋白质缀合物。有关更多信息，请参见M.‐A的全文。Kasper，C.P.R.Hackenberger等。图片由Barth van Rossum设计和创作。

更新日期：2019-12-30

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