Structural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stability

Organic & Biomolecular Chemistry
Elisabetta TobaldiAlain Wagner

Abstract

The biochemical characteristics of hetero-bifunctional cross-linkers used in bioconjugates are of essential importance to the desired features of the final adduct (i.e. antibody-drug conjugates). These include stability in biological media, chemical and biological reactivities, cleavability under defined conditions, and solubility. In our previous work, we introduced a new amino-to-thiol linker, maleimidomethyl dioxane (MD), as an alternative to classical maleimide conjugation, with increased hydrophilicity and serum stability due to succinimidyl ring-opening. In this work, we investigate the generality of linkers containing a dioxo-ring with regard to their ability to self-hydrolyze and their surprising stability at a low pH. We synthesized four FRET probes which allowed us to address the stability of the dioxo-ring and to study the maleimide ring-opening and the thiol-exchange processes by means of detecting and measuring the generation of fluorescence. It was found that the ring expansion (from a 5- to a 6-membered ring) improved the stability of the probes in aqueous media, and the increase of the chain length between the dioxo-ring and the succinimide ring (from methylene to ethylene) decreased the rate of succinimidyl rin...Continue Reading

References

Aug 26, 2011·Bioconjugate Chemistry·Aaron D Baldwin, Kristi L Kiick
Dec 17, 2014·Bioconjugate Chemistry·Shaun D FontaineDaniel V Santi
Sep 4, 2015·Bioconjugate Chemistry·Oleksandr KonievAlain Wagner
Mar 8, 2016·PloS One·David S JonesPatrick E Duffy

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Citations

Aug 11, 2018·Chemistry : a European Journal·João M J M RavascoPedro M P Gois
Jun 30, 2018·Bioconjugate Chemistry·Kévin RenaultCyrille Sabot
Jul 25, 2019·Bioconjugate Chemistry·Igor DovganAlain Wagner

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Methods Mentioned

BETA
Fluorescence
NMR
FRET

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