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5-Hydroxy-pyrrolone based building blocks as maleimide alternatives for protein bioconjugation and single-site multi-functionalization.

ABSTRACT: Recent dramatic expansion in potential uses of protein conjugates has fueled the development of a wide range of protein modification methods; however, the desirable single-site multi-functionalization of proteins has remained a particularly intransigent challenge. Herein, we present the application of 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones (5HP2Os) as advantageous alternatives to widely used maleimides for the chemo- and site-selective labeling of cysteine residues within proteins. A variety of 5HP2O building blocks have been synthesized using a one-pot photooxidation reaction starting from simple and readily accessible furans and using visible light and oxygen. These novel reagents display excellent cysteine selectivity and also yield thiol conjugates with superior stability. 5HP2O building blocks offer a unique opportunity to introduce multiple new functionalities into a protein at a single site and in a single step, thus, significantly enhancing the resultant conjugate's properties.

SUBMITTER: De Geyter E

PROVIDER: S-EPMC8179572 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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5-Hydroxy-pyrrolone based building blocks as maleimide alternatives for protein bioconjugation and single-site multi-functionalization.

De Geyter Ewout E Antonatou Eirini E Kalaitzakis Dimitris D Smolen Sabina S Iyer Abhishek A Tack Laure L Ongenae Emiel E Vassilikogiannakis Georgios G Madder Annemieke A

Chemical science 20210304 14

Recent dramatic expansion in potential uses of protein conjugates has fueled the development of a wide range of protein modification methods; however, the desirable single-site multi-functionalization of proteins has remained a particularly intransigent challenge. Herein, we present the application of 5-hydroxy-1,5-dihydro-2<i>H</i>-pyrrol-2-ones (5HP2Os) as advantageous alternatives to widely used maleimides for the chemo- and site-selective labeling of cysteine residues within proteins. A vari ...[more]

PMID: 34163760

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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 α-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-α-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

5-Hydroxy-pyrrolone based building blocks as maleimide alternatives for protein bioconjugation and single-site multi-functionalization.

Publications

5-Hydroxy-pyrrolone based building blocks as maleimide alternatives for protein bioconjugation and single-site multi-functionalization.

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