X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad.

Structure-Activity Relationship Studies of 2,4,5-Trisubstituted Pyrimidine Derivatives Leading to the Identification of a Novel and Potent Sirtuin 5 Inhibitor against Sepsis-Associated Acute Kidney Injury.

Sepsis-associated acute kidney injury (AKI) is a serious clinical problem without effective drugs. Inhibition of sirtuin 5 (SIRT5) has been confirmed to protect against AKI, suggesting that SIRT5 inhibitors might be a promising therapeutic approach for AKI. Herein, structural optimization was performed on our previous compound (IC = 3.

Early left bundle branch pacing in heart failure with mildly reduced ejection fraction and left bundle branch block.

Background: Left bundle branch pacing (LBBP) achieves resynchrony and improves cardiac function in heart failure (HF) patients with reduced ejection fraction (EF) by correcting left bundle branch block (LBBB). Few data on the efficacy of early LBBP in HF with mildly reduced EF (HFmrEF) and LBBB have been reported.

Objective: The purpose of this study was to explore the efficacy of early LBBP in patients with HFmrEF and LBBB.

Simultaneous Microcystin Degradation and Inhibition with the Single Enzyme Microcystinase A.

Harmful blooms (HMBs) seriously threaten the ecology of environments and human health. Microcystins (MCs) produced by are powerful mediators of HMB induction and maintenance. In this study, microcystinase A (MlrA), an enzyme with MC-degrading ability, was successfully obtained at over 90% purity for the first time through overexpression in K12 TB1.