Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 19, Pages 10850-10857Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202016936
Keywords
Bioconjugation; esters; macrocyclization; NHS-Activated-Acrylamides; stapling
Categories
Funding
- Fundacao para a Ciencia e a Tecnologia, Ministerio da Ciencia e da Tecnologia, Portugal [SFRH/BD/132710/2017, SFRH/BPD/102296/2014, iMed.ULisboa UIDB/04138/2020, UIDP/04138/2020, PTDC/QUI-QOR/29967/2017]
- ERC [GA 681679]
- program Investissements d'Avenir by the French Government
- Spanish MCIU [RTI-2018-099592-B-C21]
- ANR [ANR-10-IDEX-0001-02 PSL]
- [LISBOA-01-0145-FEDER-029967]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/132710/2017, SFRH/BPD/102296/2014, PTDC/QUI-QOR/29967/2017] Funding Source: FCT
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NHS-activated acrylamides, combining Michael acceptors and NHS activated esters, offer fast and chemoselective amino-sulfhydryl stapling on peptides and proteins under aqueous conditions, showing versatility and compatibility with other cysteine selective reagents for orthogonal dual-modifications. This strategy allows for late-stage functionalization of bioconjugates with various molecules, demonstrating a powerful tool in designing functional peptides and proteins.
Widely used reagents in the peptide functionalization toolbox, Michael acceptors and N-hydroxysuccinimide (NHS) activated esters, are combined in NHS-activated acrylamides for efficient chemoselective amino-sulfhydryl stapling on native peptides and proteins. NHS-activated acrylamides allow for a fast functionalization of N-terminal cysteines (k(2)=1.54 +/- 0.18x10(3) M-1 s(-1)) under dilute aqueous conditions, enabling selectivity over other nucleophilic amino acids. Additionally, the versatility of these new bioconjugation handles was demonstrated in the cross-linking of in-chain or C-terminal cysteines with nearby lysine residues. NHS-activated acrylamides are compatible with the use of other cysteine selective reagents, allowing for orthogonal dual-modifications. This strategy was successfully applied to the late-stage functionalization of peptides and proteins with a PEG unit, fluorescent probe, and cytotoxic agent. The level of molecular control offered by NHS-activated acrylamides is expected to promote amino-sulfhydryl stapling technology as a powerful strategy to design functional bioconjugates.
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