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A Ligand-Directed Nitrophenol Carbonate for Transient In Situ Bioconjugation and Drug Delivery

preprint
revised on 16.07.2020 and posted on 17.07.2020 by Anthony J. Burt, Parvaneh Ahmadvand, Larissa K. Opp, ChulHee Kang, Rock Mancini
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 time-dependent release of bioavailable immunostimulant both spectroscopically and with an immune cell line over 48 h. Avidin co-crystalized with the biotin 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.

Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA234115. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Crystallography was supported by a grant from NSF (CHE 1804699) and Murdock Charitable Trust. X-ray data collection used resources of the Advanced Light Source (beamline 5.0.2), which is a DOE Office of Science User Facility under contract no. DE-AC02-05CH11231

We acknowledge the NMR facility at Washington State University. The WSU NMR Center equipment is supported by NIH grants RR0631401 and RR12948, NSF grants CHE-9115282 and DBI-9604689, the Murdock Charitable Trust, and private donors Don and Marianna Matteson

History

Email Address of Submitting Author

Rmancini@wsu.edu

Institution

Washington State University

Country

United States

ORCID For Submitting Author

https://orcid.org/0000-0002-3557-8123

Declaration of Conflict of Interest

The authors declare no conflict of interest

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