Scientists Engineer Synthetic Molecules That Release Cancer-Fighting Compounds on Demand
Researchers have created artificial molecules that activate powerful antimicrobial compounds only in the presence of specific bacterial enzymes—a breakthrough that could enable safer, more targeted drugs. The advance sidesteps a long-standing limitation: natural versions of these compounds are unstable and difficult to control, constraining their use in pharmaceuticals and food preservation.
Originaltitel: Bioresponsive <i>pseudo</i> Glucosinolates ( <i>ps</i> GSLs) Release Isothiocyanates (ITCs) in the Presence of Nitroreductases
ABSTRACT Glucosinolates (GSLs) are plant secondary metabolites that release bioactive isothiocyanates (ITCs) upon myrosinase‐mediated activation. While ITCs display diverse antimicrobial and chemoprotective activities, their application is limited by dependence on myrosinase and intrinsic hydrolytic instability. Here, we introduce pseudoglucosinolates (psGSLs), a synthetic platform that mimics the natural GSL activation mechanism but replaces the thioglucosidic trigger with an enzyme‐responsive para ‐aminobenzylthiol motif. Using nitroreductase (NfsB) as a noncanonical activating enzyme, we synthesized and characterized a series of nitro‐masked psGSLs, including azide‐, alkyne‐, and fluorophore‐functionalized derivatives. Enzymatic reduction induces a self‐immolative 1,6‐elimination and subsequent thio‐Lossen rearrangement, releasing ITCs under physiological conditions. The liberated ITCs covalently modify peptides and proteins, showing predominant lysine reactivity in chemoproteomic analyses of the Staphylococcus aureus proteome, including functional sites of essential proteins. Fluorescent probes enabled visualization of enzyme‐dependent protein labeling and demonstrated nitroreductase‐triggered ITC release in vivo in Caenorhabditis elegans . Together, psGSLs establish a modular, bioresponsive prodrug and chemical biology platform for enzyme‐controlled ITC delivery, expanding the scope of ITC‐based covalent modification beyond natural myrosinase‐dependent systems.