A Ligand‐Directed Nitrophenol Carbonate for Transient in situ Bioconjugation and Drug Delivery

Here we report the first use of ligand‐directed proximity accelerated bioconjugation chemistry in the tandem delivery and release of a therapeutic payload. To do this, we designed a nitrophenol carbonate for ligand‐directed in situ bioconjugation of a prodrug payload to a protein. The transient natu...

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Bibliographic Details
Published in:ChemMedChem 2020-11, Vol.15 (21), p.2004-2009
Main Authors: Burt, Anthony J., Ahmadvand, Parvaneh, Opp, Larissa K., Ryan, Austin T., Kang, ChulHee, Mancini, Rock J.
Format: Article
Language:English
Subjects:
Affinity Labelling
Avidin
Bioavailability
Bioconjugation
Biotin
Communication
Communications
Conjugation
Drug delivery
Drug delivery systems
Immune system
Immunochemistry
Immunostimulants
INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Ligands
Nitrophenol
Prodrugs
Protein A
Proteins
Time dependence
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Summary:Here we report the first use of ligand‐directed proximity accelerated bioconjugation chemistry in the tandem delivery and release of a therapeutic payload. To do this, we designed a nitrophenol carbonate for ligand‐directed in situ bioconjugation of a prodrug payload to a protein. The transient nature of our conjugation chemistry renders the protein a depot for time‐dependent release of active drug following hydrolysis and self‐immolation. In our model system, using an immunostimulant prodrug, biotin ligand, and avidin protein, we observe release of bioavailable immunostimulant both spectroscopically and with an immune cell line over 48 h. Avidin co‐crystalized with the nitrophenolate directing group verified the binding pose of the ligand and offered insight into the mechanism of in situ bioconjugation. Overall, this scaffold warrants further investigation for the time‐dependent delivery of therapeutics and use in protein ligand pairs beyond biotin and avidin used for this work. Ligand‐directed proximity accelerated bioconjugation to deliver a therapeutic payload using a novel nitrophenol carbonate derivative. In this work, we demonstrate the utility for the ligand‐directed in situ labeling of a protein avidin with an immunostimulant prodrug. This renders the target protein a depot for time‐dependent release of active drug. The mechanism is probed using crystallography, and time‐dependent drug release is demonstrated in vitro.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202000655