期刊
BIOCONJUGATE CHEMISTRY
卷 30, 期 11, 页码 2889-2896出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.9b00609
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资金
- NIH [RO1 CA174844, RO1 CA181258, RO1 CA204484]
- Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research
By exploiting a uniquely reactive lysine residue (Lys99) for site-specific attachment of small molecules, the humanized catalytic antibody h38C2 has been used as bioconjugation module in the assembly of chemically programmed antibodies and antibody-drug conjugates. Treatment of h38C2 with beta-lactam-functionalized small molecules has been previously shown to result in covalent conjugation by selective formation of a stable amide bond with the epsilon-amino group of the Lys99 residue. Here we report that heteroaryl methylsulfonyl (MS-PODA)-functionalized small molecules represent an alternative bioconjugation strategy through highly efficient, site-specific, and stable arylation of the Lys99 residue. A set of chemically programmed antibodies and antibody-drug conjugates assembled by Lys99 arylation provided proof-of-concept for the therapeutic utility of this alternative bioconjugation strategy. While being equally effective as beta-lactam-functionalized ligands for bioconjugation with catalytic antibody h38C2, the MS-PODA moiety offers distinct synthetic advantages, making it highly attractive.
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