Abstract
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.
Highlights
Bioconjugates are an alluring therapeutic modality that, relative to small molecules, suffer drawbacks in production including high cost, poor batch reproducibility, and poor shelf life; all of which hinder the development of bioconjugates as drugs.[1]
We envisioned that if this concept could be expanded to develop an affinity labeling platform that yields in situ bioconjugates capable of time-dependent drug release, this could bypass the drawbacks of producing bioconjugate drugs while still harnessing the therapeutic benefits
They have demonstrated success with soluble proteins such as carbonic anhydrase as well as membrane bound proteins such as the folate receptor with examples of in situ, in vitro, ex vivo, and in vivo labeling.[11,17]. With these liganddirected probes in mind, we designed a scaffold (Figure 1) that allows for time-dependent drug delivery via a transient in situ bioconjugate formed by ligand-directed affinity labeling
Summary
Bioconjugates are an alluring therapeutic modality that, relative to small molecules, suffer drawbacks in production including high cost, poor batch reproducibility, and poor shelf life; all of which hinder the development of bioconjugates as drugs.[1]. For this proof-of-concept work, the protein ligand pair of avidin-biotin was chosen because: 1) the avidinbiotin crystal structure is known, and verified the presence of possible peripheral nucleophiles (Nu) to the biotin binding site.[19] 2) The high affinity of biotin for avidin (Kd ≈ 10-15 M) [20] was hypothesized to lead to rapid complexation and rapid covalent labeling. The utility of LDNPC chemistry as a drug delivery technique can be proven utilizing a biotin directing group to render avidin as a time-dependent imidazoquinoline prodrug in situ.
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