Staudinger Ligation as a Method for Bioconjugation

Abstract

In 1919 the German chemist Hermann Staudinger was the first to describe the reaction between an azide and a phosphine. It was not until recently, however, that Bertozzi and co-workers recognized the potential of this reaction as a method for bioconjugation and transformed it into the so-called Staudinger ligation. The bio-orthogonal character of both the azide and the phosphine functions has resulted in the Staudinger ligation finding numerous applications in various complex biological systems. For example, the Staudinger ligation has been utilized to label glycans, lipids, DNA, and proteins. Moreover, the Staudinger ligation has been used as a synthetic method to construct glycopeptides, microarrays, and functional biopolymers. In the emerging field of bio-orthogonal ligation strategies, the Staudinger ligation has set a high standard to which most of the new techniques are often compared. This Review summarizes recent developments and new applications of the Staudinger ligation.

Small gold nanoparticles for interfacial Staudinger–Bertozzi ligation

“…The [3 + 2] Huisgen cycloaddition and the copper catalyzed [3 + 2] Huisgen cycloaddition with dipolarophiles, the strained-promoted alkyne-azide cycloaddition (SPAAC) with strained alkynes and the Staudinger-Bertozzi ligation. 10,11 While the [3 + 2] Huisgen cycloaddition and its catalyzed version are not completely compatible with AuNPs chemistry because the high temperature or the Cu(I) required to push the reaction to completion cause severe nanoparticle aggregation, 12 the SPAAC reaction presents limited chemoselectivity due to the possibility of nucleophilic attacks (especially from thiols and amines largely present in biomolecules) to the highly reactive strained triple bond. [13][14][15] A recent work of ours highlighted this issue showing how post assembly deprotection of peptides once "clicked" on the AuNP surface was necessary to efficiently synthesize a nanoparticle bioconjugate through the SPAAC reaction.…”

Structural and Kinetic Considerations for the Application of the Traceless Staudinger Ligation to Future 18F Radiolabeling Using XRD and 19F NMR

“…Independent on the variant of the Staudinger ligation (traceless or nontraceless), functionalized phosphanes act as starting material in general [6][7][8]. Furthermore, the traceless ligation can be divided in two approaches.…”

“…CONCLUSION X-ray structure determinations of the starting phosphanes and kinetic measurements of the reaction rate between fluorinated phosphane and various azides were accomplished under different reaction conditions to transfer and apply the traceless Staudinger ligation for future radiolabeling with short-lived β + -emitter fluorine-18 and other radionuclides. For this purpose, 19 F NMR was used due to the presence of 19 F in the starting material (phosphane 3) as well as in the corresponding products (7)(8)(9). The results of the measurements clearly indicate that it is possible to apply the traceless Staudinger ligation for radiolabeling purposes even in consideration of the short half-live of fluorine-18 under mild labeling conditions with a rather slow reaction rate.…”

“…The absence of a metal catalyst (e.g., Cu) is important especially for in vitro and in vivo applications, because Cu is known to be cytotoxic [5]. Therefore, the traceless variant of the Staudinger ligation [6][7][8] independently developed by Raines et al [9] and Bertozzi et al [10] is employed for several applications in chemistry, biochemistry, and (radio)pharmacy. The connection of proteins [11,12], peptides, and peptide fragments [9,13], the glycosylation [14] of amino acids and peptides [15,16], the preparation of large-sized lactams [17,18], the functionalization of polymers [19], and the introduction of radiolabels [20][21][22][23] as well as fluorescence dyes [24][25][26] makes this reaction widely applicable.…”

Dual-sugar imaging using isonitrile and azido-based click chemistries

“…21 We have recently shown that the isonitrile group can also be used as a novel chemical reporter group for glycan metabolic labelling. 22 Azides incorporated in cell surface glycoproteins can be detected using either the Staudinger ligation, 23 the copper catalysed [3 + 2] cycloaddition with alkynes (with biologically compatible catalysts) 24 or the copper-free [3 + 2] cycloaddition with strained cyclooctynes. 25 Cyclopropenes and alkenes, on the other hand, can react with tetrazines.…”