https://www.selleckchem.com/products/icec0942-hydrochloride.html Copyright © 2020 American Chemical Society.Small interfering RNAs (siRNAs) are potent therapeutic molecules, but despite recent progress, their administration in vivo remains challenging due to their low stability in the bloodstream. Thus, techniques for investigating the stability of siRNA are fundamental for the development of efficient siRNA delivery systems. We designed a simple FRET electrophoresis method to dynamically evaluate serum siRNA stability in parallel with its interaction with the serum components. Each strand of the siRNA was labeled with the fluorophore carboxyfluorescein (FAM) at the 5'-end and the quencher carboxytetramethylrhodamine (TAMRA) at the 3'-end. After incubation in serum, molecular stability was proportional to the FRET efficiency that could be quantified in-gel by ImageJ analysis. Compared to the usual gel-shift and other plate-based FRET assays, this method is more sensitive and allows investigation of the stability of serum siRNA and siRNA-based nanoparticles, as well as the extrapolation of degradation kinetics in parallel with interaction analysis. Copyright © 2020 American Chemical Society.Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure, and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP. Previously, we have reported the crystal structure of NEP bound with LBQ657, whereby we noted the presence of a subsite in S1' that has not been explored before. We were also intrigued by the zinc coordination made by one of the carboxylic acids of LBQ657, leading us to explore alternative linkers to efficiently engage zinc for NEP inhibition. Structure-guided design culminated in the synthesis of selective, orally bioavail