Enzyme-cleavable linker

H. Waldmann, B. Sauerbrei, U. Grether, Enzyme cleavable linker for solid phase synthesis, (BASF A.G., Germany), Ger. Offen. 1998, CAN 128 114573. 

Linker 31 was attached via a carbamate-ester to an amino-functionalized polymeric support (Fig. 7). Treatment with lithium hydroxide liberated linker acid 32. First attempts to use this enzyme cleavable linker on crosslinked... 

Cross-linking of PEG with enzyme cleavable linkers (peptides)... 

Methods for the introduction of enzyme cleavable linkers between polymer blocks. 

By contrast, exo-linkers do not restrict the structure of the reactant and can be cleaved by more readily-available exo-enzymes, which act at the end of a chain or externally (Tab. 10.2). Furthermore exo-cleavable linkers yield untagged products upon cleavage from the soHd support... 

Small antibody fragments can be converted into therapeutic agents by modification with suitable radionuclides, drugs (using cleavable linkers or liposomal preparations), enzymes catalyzing prodrug conversion, cytokines, pro-coagulant factors, photosensitizers, and other classes of... 

FIGURE 6.28 Different types of bioresponsive hydrogels that change properties in response to (I) small molecules via receptor/ligand interactions (II) (ceU-secreted) enzymes via cleavable linkers and (III) small molecules that are convated by immobilized enzymes. The macroscopic response (sweUing/coUapse of the hydrogel) is shown. Source Ulijn et al. [113]. Reproduced with permission of Elsevier. 

In principle, linker groups are polymer-enlarged versions of blocking functions used in regular solution-phase chemistry. Therefore, enzymatic transformations that may be employed for the removal of protecting groups in solution, in principle may also open up alternative opportunities for releasing compounds from polymeric supports. The linkers developed so far can be divided into exo- and endo-linkers (Fig. 10.1) cleavable by exo- respectively endo-enzymes, as proposed by Flitsch et al. [6]. 

In independent and simultaneous investigations Fhtsch et al. [41-42] and Wald-mann et al. [43—44] developed selectively cleavable exo-linkers, which can be cleaved with penicillin G acylase, a commercially available and widely used enzyme [45]. 

Table 3.8. Linkers for carboxylic acids cleavable by enzymes.

These requirements have stimulated the research for new chemical strategies of coupling, and in particular for linkers that are easily cleaved. These include esters, lisosomotropic peptides that are stable in plasma but cleavable inside the cells by cathepsins [37], and spacers that can be directly cleaved under acidic conditions or by anchimeric assistance such as ds-citraconic acid amides or hydrazones derivatives [38]. Furthermore, pro-drug approaches or trimethyl lock systems have been developed where the carrier is cleaved in two steps, initially by water or enzymes and later by a chemical mechanism [39]. 

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