Discovery of α-Amidobenzylboronates as Highly Potent Covalent Inhibitors of Plasma Kallikrein.

Hereditary angioedema (HAE), a rare genetic disorder, is associated with uncontrolled plasma kallikrein (PKa) enzyme activity leading to the generation of bradykinin swelling in subcutaneous and submucosal membranes in various locations of the body. Herein, we describe a series of potent α-amidobenzylboronates as potential covalent inhibitors of PKa. These compounds exhibited time-dependent inhibition of PKa (compound IC 66 nM at 1 min, 70 pM at 24 h).

PET ligands [F]LSN3316612 and [C]LSN3316612 quantify -linked-β--acetyl-glucosamine hydrolase in the brain.

We aimed to develop effective radioligands for quantifying brain -linked-β--acetyl-glucosamine (-GlcNAc) hydrolase (OGA) using positron emission tomography in living subjects as tools for evaluating drug target engagement. Posttranslational modifications of tau, a biomarker of Alzheimer's disease, by -GlcNAc through the enzyme pair OGA and -GlcNAc transferase (OGT) are inversely related to the amounts of its insoluble hyperphosphorylated form. Increase in tau -GlcNAcylation by OGA inhibition is believed to reduce tau aggregation.

Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs.

Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer's disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion.

Capturing complexity: field-testing the use of 'structure from motion' derived virtual models to replicate standard measures of reef physical structure.

Reef structural complexity provides important refuge habitat for a range of marine organisms, and is a useful indicator of the health and resilience of reefs as a whole. Marine scientists have recently begun to use 'Structure from Motion' (SfM) photogrammetry in order to accurately and repeatably capture the 3D structure of physical objects underwater, including reefs. There has however been limited research on the comparability of this new method with existing analogue methods already used widely for measuring and monitoring 3D structure, such as 'tape and chain rugosity index (RI)' and graded visual assessments.