Staudinger-Phosphonite Reactions for the Chemoselective Transformation of Azido-Containing Peptides and Proteins

Vallée, M. Robert J.; Majkut, Paul; Wilkening, Ina; Weise, Christoph; Müller, Gregor; Hackenberger, Christian P. R.

doi:10.1021/ol2020175

Cited by 44 publications

(50 citation statements)

References 35 publications

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“…[19] By taking advantage of this,w eh ave used borane-protected ethynylphosphonites for the sequential coupling of two azide-containing molecules,i ncluding probes,p olymers,o rp roteins. [19] By taking advantage of this,w eh ave used borane-protected ethynylphosphonites for the sequential coupling of two azide-containing molecules,i ncluding probes,p olymers,o rp roteins.…”

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Cysteine‐Selective Phosphonamidate Electrophiles for Modular Protein Bioconjugations

et al. 2019

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We describe anew technique in protein synthesis that extends the existing repertoire of methods for protein modification:Achemoselective reaction that induces reactivity for as ubsequent bioconjugation. An azide-modified building blockr eacts first with an ethynylphosphonite through aS taudinger-phosphonite reaction (SPhR) to give an ethynylphosphonamidate.T he resulting electron-deficient triple bond subsequently undergoes ac ysteine-selective reaction with proteins or antibodies.W ed emonstrate that ethynylphosphonamidates display excellent cysteine-selective reactivity combined with superior stability of the thiol adducts,w hen compared to classical maleimide linkages.T his turns our technique into av ersatile and powerfult ool for the facile construction of stable functional protein conjugates.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.Figure 4. a) Synthetic scheme for phosphonamidate attachmentofthe Cy5f luorophore to trastuzumab(anti-Her2 antibody) to generate an AFC. b) Immunostaining of fixed cells either over-expressing the cell-surface receptor Her2 (BT474) or exhibiting low Her2 expression levels (MDAMB468). The merged images show the signal from the DNA stain DAPI in blue and the Cy5signal in red. Scale bar:10mm. c) Synthetic scheme for the attachmento fphosphonamidite-modified cCPPs 8 and 9 to aeGFP mutant with asingle addressable cysteine. d) Fluorescence imaging of HeLa cells after incubation with eGFP alone and eGFP-cTat at 50 mm.I mages show the GFP channel in green and the Hoechst 33342 nuclear stain in blue. Scale bar:2 0mm. Forfurther information see the SupportingInformation. Angewandte Chemie Communications

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Cysteine‐Selective Phosphonamidate Electrophiles for Modular Protein Bioconjugations

et al. 2019

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“…[19] [21] Bisher wurde dieses Problem durch die Isolierung von luftbeständigen, borangeschützten Phosphoniten gelçst, die mit Hilfe von starken Basen vor der SPhR entschützt werden mussten. [19] [21] Bisher wurde dieses Problem durch die Isolierung von luftbeständigen, borangeschützten Phosphoniten gelçst, die mit Hilfe von starken Basen vor der SPhR entschützt werden mussten.…”

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Cysteinselektive phosphonamidatbasierte Elektrophile für modulare Biokonjugationen

et al. 2019

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Wirb eschreiben eine neue Methode zur Proteinsynthese,d ie das bestehende Repertoire an Mçglichkeiten zur Proteinmodifikation erweitert:E ine chemoselektive Reaktion induziert Reaktivitätf üre ine nachfolgende Biokonjugation. Hierbei reagiert ein azidmodifizierter Baustein zunächst mit einem Ethinylphosphonit in einer Staudinger-Phosphonit-Reaktion (SPhR) zu einem Ethinylphosphonamidat. Die so entstehende elektronenarme Dreifachbindung modifiziert anschließend in einer cysteinselektiven Reaktion Proteine und Antikçrper.W ir zeigen, dass Ethinylphosphonamidate eine herausragende SelektivitätfürCysteine aufweisen, gepaart mit einer überragenden Stabilitätd er Thiol-Addukte im Vergleich zu klassischen Maleimid-Konjugaten. Diese Erkenntnis macht unsere Technik zu einer vielseitigen und leistungsstarken Methode fürdie mühelose Herstellung von stabilen, funktionalen Proteinkonjugaten.

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“…62 Finally, we were able to use Staudinger phosphonite reactions for the conjugation of short PEG chains to proteins, in which aryl or triazole phosphonites are used in the reaction with aryl azides. 63,64 Recently, we have studied the impact of PEG chain length at the phosphoramidate branching point on intracellular distribution and activity of proapoptotic peptides. 65 Interestingly, the intracellular application of PEGs for the stabilization of peptides had not been demonstrated before.…”

Section: ■ Branched Phosphite Peg Reagents For Chemoselective Staudinmentioning

confidence: 99%

Site-specific PEGylation of Proteins: Recent Developments

Nischan

Hackenberger

2014

J. Org. Chem.

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The attachment of linear polyethylene glycol (PEG) to peptides and proteins for their stabilization for in vivo applications is a milestone in pharmaceutical research and protein-drug development. However, conventional methods often lead to heterogeneous PEGylation mixtures with reduced protein activity. Current synthetic efforts aim to provide site-specific approaches by chemoselective targeting of canonical and noncanonical amino acids and to improve the PEG architecture. This synopsis highlights recent work in this area, which also resulted in improved pharmacokinetics of peptide and protein therapeutics.

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Staudinger-Phosphonite Reactions for the Chemoselective Transformation of Azido-Containing Peptides and Proteins

Cited by 44 publications

References 35 publications

Cysteine‐Selective Phosphonamidate Electrophiles for Modular Protein Bioconjugations

Cysteine‐Selective Phosphonamidate Electrophiles for Modular Protein Bioconjugations

Cysteinselektive phosphonamidatbasierte Elektrophile für modulare Biokonjugationen

Site-specific PEGylation of Proteins: Recent Developments

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