N-Hydroxysuccinimide-Modified Ethynylphosphonamidates Enable the Synthesis of Configurationally Defined Protein Conjugates.
antibody-drug conjugates
bioconjugation
cysteine-selective linkers
protein conjugation
synthesis design
Journal
Chembiochem : a European journal of chemical biology
ISSN: 1439-7633
Titre abrégé: Chembiochem
Pays: Germany
ID NLM: 100937360
Informations de publication
Date de publication:
15 01 2020
15 01 2020
Historique:
received:
20
09
2019
pubmed:
30
10
2019
medline:
6
1
2021
entrez:
30
10
2019
Statut:
ppublish
Résumé
Herein, the application of N-hydroxysuccinimide-modified phosphonamidate building blocks for the incorporation of cysteine-selective ethynylphosphonamidates into lysine residues of proteins, followed by thiol addition with small molecules and proteins, is reported. It is demonstrated that the building blocks significantly lower undesired homo-crosslinking side products that can occur with commonly applied succinimidyl 4-(N-maleimidomethyl)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 subsequent thiol addition. Furthermore, a method to separate the phosphonamidate enantiomers to be able to synthesize protein conjugates in a defined configuration has been developed. Finally, the building blocks are applied to the construction of functional antibody-drug conjugates, analogously to FDA-approved, SMCC-linked Kadcyla, and to the synthesis of a functional antibody-protein conjugate.
Identifiants
pubmed: 31661184
doi: 10.1002/cbic.201900587
pmc: PMC7003776
doi:
Substances chimiques
Amides
0
Phosphoric Acids
0
Succinimides
0
enhanced green fluorescent protein
0
Green Fluorescent Proteins
147336-22-9
phosphoramidic acid
9Q189608GB
Ethylene Glycol
FC72KVT52F
N-hydroxysuccinimide
MJE3791M4T
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113-119Informations de copyright
© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
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