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oxSTEF Reagents Are Tunable and Versatile Electrophiles for Selective Disulfide-Rebridging of Native Proteins

Authors :
Marija Nisavic
Gustav J. Wørmer
Cecilie S. Nielsen
Sofie M. Jeppesen
Johan Palmfeldt
Thomas B. Poulsen
Source :
Nisavic, M, Wørmer, G J, Nielsen, C S, Jeppesen, S M, Palmfeldt, J & Poulsen, T B 2023, ' oxSTEF Reagents Are Tunable and Versatile Electrophiles for Selective Disulfide-Rebridging of Native Proteins ', Bioconjugate Chemistry, vol. 34, no. 6, pp. 994-1003 . https://doi.org/10.1021/acs.bioconjchem.3c00005
Publication Year :
2023
Publisher :
American Chemical Society (ACS), 2023.

Abstract

Site-selective disulfide rebridging has emerged as a powerful strategy to modulate the structural and functional properties of proteins. Here, we introduce a novel class of electrophilic reagents, designated oxSTEF, that demonstrate excellent efficiency in disulfide rebridging via double thiol exchange. The oxSTEF reagents are prepared using an efficient synthetic sequence which may be diverted to obtain a range of derivatives allowing for tuning of reactivity or steric bulk. We demonstrate highly selective rebridging of cyclic peptides and native proteins, such as human growth hormone, and the absence of cross-reactivity with other nucleophilic amino acid residues. The oxSTEF conjugates undergo glutathione-mediated disintegration under tumor-relevant glutathione concentrations, which highlights their potential for use in targeted drug delivery. Finally, the α-dicarbonyl motif of the oxSTEF reagents enables "second phase" oxime ligation, which furthermore increases the thiol stability of the conjugates significantly.

Details

ISSN :
15204812 and 10431802
Database :
OpenAIRE
Journal :
Bioconjugate Chemistry
Accession number :
edsair.doi.dedup.....ca80830788253294884664db53237ebb
Full Text :
https://doi.org/10.1021/acs.bioconjchem.3c00005