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Site-Specific In Vivo Bioorthogonal Ligation via Chemical Modulation.

ABSTRACT: A critical limitation of bioorthogonal click chemistry for in vivo applications has been its low reaction efficiency due to the pharmacokinetic barriers, such as blood distribution, circulation, and elimination in living organisms. To identify key factors that dominate the efficiency of click chemistry, here a rational design of near-infrared fluorophores containing tetrazine as a click moiety is proposed. Using trans-cyclooctene-modified cells in live mice, it is found that the in vivo click chemistry can be improved by subtle changes in lipophilicity and surface charges of intravenously administered moieties. By controlling pharmacokinetics, biodistribution, and clearance of click moieties, it is proved that the chemical structure dominates the fate of in vivo click ligation.

SUBMITTER: Koo H

PROVIDER: S-EPMC5541365 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Site-Specific In Vivo Bioorthogonal Ligation via Chemical Modulation.

Koo Heebeom H Lee Jeong Heon JH Bao Kai K Wu Yunshan Y El Fakhri Georges G Henary Maged M Yun Seok Hyun SH Choi Hak Soo HS

Advanced healthcare materials 20160829 19

A critical limitation of bioorthogonal click chemistry for in vivo applications has been its low reaction efficiency due to the pharmacokinetic barriers, such as blood distribution, circulation, and elimination in living organisms. To identify key factors that dominate the efficiency of click chemistry, here a rational design of near-infrared fluorophores containing tetrazine as a click moiety is proposed. Using trans-cyclooctene-modified cells in live mice, it is found that the in vivo click ch ...[more]

PMID: 27568818

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Project description:Precise control of covalent bond formation in the presence of multiple functional groups is pertinent in the development of many next-generation bioconjugates and materials. Strategies derived from bioorthogonal chemistries are contributing greatly in that regard; however, the gain of chemoselectivity is often compromised by the slow rates of many of these existing chemistries. Recent work on a variation of the classical aldehyde/ketone condensation based on ortho-carbonylphenylboronic acids has uncovered markedly accelerated rates compared to those of the simple carbonyl counterparts. The products of these reactions are distinct, often in the form of boron-nitrogen heterocycles. In particular, we have shown that 2-formylphenylboronic acid (2fPBA), when coupled with an ?-amino-hydrazide, produces a unique zwitterionic and stable 2,3,1-benzodiazaborine derivative. In this work, we apply this chemistry to generate chemically defined and functional bioconjugates, herein illustrated with immunoconjugates. We show that an antibody and a fluorophore (as payload) equipped with the relevant reactive handles undergo rapid conjugation at near-stoichiometric ratios, displaying a reaction half-life of only ?5 min with 2 equiv of the linker payload. Importantly, the reaction can be extended to multicomponent labeling by partnering with the popular strain-promoted azide-alkyne cycloaddition and tetrazine- trans-cyclooctene (Tz-TCO) ligation. The mutual orthogonality to both of these chemistries allows simultaneous triple bioorthogonal conjugations, a rare feat thus far that will widen the scope of various multilabeling applications. Further collaboration with the Tz-TCO reaction enables rapid one-pot synthesis of a site-specific dual-payload antibody conjugate. Altogether, we envision that the 2fPBA-?-amino-hydrazide ligation will facilitate efficient assembly of diverse bioconjugates and materials, enabling access to more complex modalities via partnership with other orthogonal chemistries.

Dataset Information

Site-Specific In Vivo Bioorthogonal Ligation via Chemical Modulation.

Publications

Site-Specific In Vivo Bioorthogonal Ligation via Chemical Modulation.

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