KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE-mediated Activation.

Mast cell (MC)-driven allergic diseases are constantly expanding and require the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation via crosslinking of the high-affinity receptor for IgE (FcεRI) is fundamentally regulated by SRC family kinases, for example, LYN and FYN, exhibiting positive and negative functions. We report that KIRA6, an inhibitor for the endoplasmic reticulum stress sensor IRE1α, suppresses IgE-mediated MC activation by inhibiting both LYN and FYN.

Small-molecule modulators of TRMT2A decrease PolyQ aggregation and PolyQ-induced cell death.

Polyglutamine (polyQ) diseases are characterized by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats encoding for an uninterrupted prolonged polyQ tract. We previously identified TRMT2A as a strong modifier of polyQ-induced toxicity in an unbiased large-scale screen in . This work aimed at identifying and validating pharmacological TRMT2A inhibitors as treatment opportunities for polyQ diseases in humans.

Dynorphin Neuropeptides Decrease Apparent Proton Affinity of ASIC1a by Occluding the Acidic Pocket.

Prolonged acidosis, as it occurs during ischemic stroke, induces neuronal death via acid-sensing ion channel 1a (ASIC1a). Concomitantly, it desensitizes ASIC1a, highlighting the pathophysiological significance of modulators of ASIC1a acid sensitivity. One such modulator is the opioid neuropeptide big dynorphin (Big Dyn) which binds to ASIC1a and enhances its activity during prolonged acidosis.

The Conorfamide RPRFa Stabilizes the Open Conformation of Acid-Sensing Ion Channel 3 via the Nonproton Ligand-Sensing Domain.

Acid-sensing ion channel 3 (ASIC3) is a proton-gated Na channel with important roles in pain. ASIC3 quickly desensitizes in less than a second, limiting its capacity to sense sustained acidosis during pain. RFamide neuropeptides are modulators of ASIC3 that slow its desensitization and induce a variable sustained current.

Heteroaromatic π-stacking energy landscapes.

In this study we investigate π-stacking interactions of a variety of aromatic heterocycles with benzene using dispersion corrected density functional theory. We calculate extensive potential energy surfaces for parallel-displaced interaction geometries. We find that dispersion contributes significantly to the interaction energy and is complemented by a varying degree of electrostatic interactions.

Cleavage entropy as quantitative measure of protease specificity.

A purely information theory-guided approach to quantitatively characterize protease specificity is established. We calculate an entropy value for each protease subpocket based on sequences of cleaved substrates extracted from the MEROPS database. We compare our results with known subpocket specificity profiles for individual proteases and protease groups (e.