Researchers at China Pharmaceutical University and Yunnan Minzu University developed esterase-activated cyanide prodrugs that release hydrogen cyanide with tunable kinetics and provide real-time fluorogenic tracking, according to a study published in Nature Communications.
Hydrogen cyanide functions as a mammalian gasotransmitter with biphasic biological effects, but experimental investigation has faced constraints due to a lack of controllable delivery tools. The research team designed donor molecules that synchronously release cyanide and regenerate an intramolecular charge transfer (ICT)-based fluorophore upon esterase activation. Steric modulation at the cyanohydrin α-carbon allowed the authors to control the release rate over an order of magnitude, spanning observed rate constants (kobs) from 0.04 to 0.83 min−1.
In cell-based assays, biological outcomes correlated directly with the rate of cyanide generation rather than the nominal donor concentration. Low release rates stimulated cell proliferation, whereas higher generation rates produced cellular toxicity. Cytoprotection occurred within an experimentally observed generation rate between 0.3 and 0.7 nmol mg−1 protein h−1 under the tested conditions.
In an in vivo middle cerebral artery occlusion (MCAO) model, the researchers evaluated a lead donor compound designated Et-1. Administered at a dose of 1 μmol kg−1 (0.3 mg kg−1), Et-1 reduced infarct volume and attenuated both lipid peroxidation and inflammation.
The study was authored by co-lead contributors Xidan Tong, Wen Peng, and Jinkang Feng alongside senior researcher Yueqin Zheng and colleagues. Research funding was provided by the National Natural Science Foundation of China under grant numbers 22577156 and 22377147, the Lingang Laboratory under grant number LGL-2614-16, and the Fundamental Research Funds for the Central Universities.
