Staudinger Ligation and Reactions – From Bioorthogonal Labeling to Next‐Generation Biopharmaceuticals

Abstract

In this review, we highlight groundbreaking discoveries and applications of Staudinger reactions in the molecular life sciences, starting from the engineering of the Staudinger ligation as a bioorthogonal reaction until most recent applications in modern bioconjugation methods to generate next-generation biopharmaceuticals. Bioorthogonal reactions refer to a set of chemoselective transformations in biological environments able to take place in presence of naturally occurring functional groups. The Staudinger ligation set a new paradigm of such transformations, resulting in the development of various labeling and bioconjugation strategies for the modification of (bio-)molecules of interest.

Clicking in harmony: exploring the bio-orthogonal overlap in click chemistry

“…One of the key advantages of Staudinger ligation is its selectivity, as the azide group is virtually absent in biological molecules, and the triarylphosphine is unreactive toward most other functional groups, thereby ensuring minimal interference with the cellular processes. 66 This selectivity allows for precise and targeted modifications of biomolecules, such as labelling specific proteins with fluorophores or other tags, tracking their localization, and probing their interactions with other molecules in a non-invasive manner.…”

A Brief Guide to Preparing a Peptide–Drug Conjugate

“…For instance, the reaction yields rise when a glycine residue is present at the conjugation point, as ligations with less sterically hindered amino acids are usually the most efficient. [30,31] These observations make the structure of the peptidic reactant a key point for choosing a Staudinger ligation over other conjugation reactions. Her research interests are focused on the design and synthesis of integrin-targeted small molecule peptidomimetics and their covalent conjugates for biomedical applications.…”

“…The rate of traceless Staudinger ligation is usually low ( k ∼7.7×10 −3 M −1 s −1 ), [29] but the kinetics is influenced both by the structure of the phosphine and of the peptide. For instance, the reaction yields rise when a glycine residue is present at the conjugation point, as ligations with less sterically hindered amino acids are usually the most efficient [30,31] . These observations make the structure of the peptidic reactant a key point for choosing a Staudinger ligation over other conjugation reactions.…”

“Click” for precise photodynamic therapy

“…The use of non-naturally occurring functionalities can lead to more specific and efficient bioconjugation. A wide range of click reactions, including the classical Staudinger ligation, CuAAC, SPAAC and IEDDA reactions, 2,3,29 as well as the light-and oxidation-promoted counterparts 30,31 have been utilised to introduce various biological moieties to molecular and nanomaterials. Systems that contain multiple bioorthogonal handles have also been reported, which can be used to prepare multifunctional conjugates via the respective click reactions.…”