Selective Protein Degradation by Ligand‐Targeted Enzymes: Towards the Creation of Catalytic Antagonists

Abstract

COVER PICTUREThe cover picture shows a ligand-targeted proteinase enzyme or ™catalytic antagonist∫ acting as a molecular angler fish: By precisely positioning different binding ligands (L) around the active site ™mouth∫ of a degradative proteinase enzyme, target proteins (TP) can be plucked from solution, locked in position adjacent to the catalytic triad ™jaws∫, and in this way readily and specifically degraded. The hunting strategy of the deep sea angler fish, which uses a lure above its mouth, illustrates this principle. Further details can be found in the article by B. Davis, R. R. Bott, J. B. Jones et. al. on pp. 533 ± 537. REVIEWS Don't get stressed! Stress is often linked by anecdote to degeneration and disease. Key molecular, cellular and medical evidence is described in this review that gives firm support for this linkage and suggests that key stress hormones such as cortisol or corticosterone acting in synergy with the action of cytokines (see figure) may trigger and/or promote many diseases.N. Lozovaya, A. D. Miller* ± 484Chemical Neuroimmunology: Health in a NutshellChemBioChem is a European journal of chemical biology; it is co-owned by a group of European scientific societies and published by WILEY-VCH. Contributions in ChemBioChem cover chemical biology and biological chemistry, medicinal chemistry, bioinorganic and bioorganic chemistry, biochemistry, molecular and structural biology, that is, research of the overlapping areas between biology and chemistry.

Concepts of Catalysis in Site-Selective Protein Modifications

“…The principles of ordering, orientation, selectivity and mimicry set out here in many parts apply also to solely biocatalytic strategies. 62 Indeed, one might consider the exploitation of Ubq-mediated proteolysis in so-called Protacs 63 or the repurposing of proteases to target their degradation to chosen proteins 64 as examples of man-made, “new-to-nature” modes of hydrolytic protein modification.…”

Extracellular purine and pyrimidine catabolism in cell culture

“…This co‐aggregation inhibition is thought to be the most potent to date. In a parallel strategy, such protease targeting via homing carbohydrate ligands has also been further exemplified by equipping SBL with a mannose targeting ligand 21. The resulting mannosylated protease showed increased degradation of a protein target, the mannose binding lectin concanavalin A (Con A), although the monovalent display used in this instance gave only a modest 1.5‐fold increase in selectivity.…”

Chemical approaches to mapping the function of post‐translational modifications

“…For instance, a library of ‘catalytic antagonists’ was engineered for affinity proteolysis by incorporation of a variety of ligands onto protease SBL, including examples of natural PTMs such as biotinylation and d ‐mannosylation (Fig. 3) [49]. The pendant ligands allowed SBL to selectively bind a protein target or partner and, by virtue of proximity, catalyze enhanced hydrolytic degradation of the target protein.…”

“…(B) A ring of modification sites (blue) around the active site (red) of the modified protease was explored. Taken from [49].…”