intravital-two-photon-imaging-touch-sensory-axon-morphology-mouse

Intravital Two-Photon Imaging of Touch Sensory Axon Morphology in Mouse Skin

Low-threshold mechanoreceptors (LTMRs) are somatosensory neurons that detect innocuous light touch stimuli such as vibration, hair deflection, and ...

Vanderbilt University

This study focuses on developing highly potent inhibitors targeting peptidyl arginine deiminases (PADs), particularly PAD4 and PAD1, which play critical roles in citrullination-linked diseases such as cancer and autoimmune disorders. A series of benzylamine- and benzimidazole-substituted compounds were synthesized and evaluated for their inhibitory activity. Key findings include the identification of naphthalene and quinoline-based scaffolds with hydroxyl substitutions, which exhibited superior inhibition of PAD1 and PAD4 (IC values as low as 0.273 μM and 0.204 μM, respectively), compared with their precursor, Cl-amidine. While the most potent compounds 13 and 16 showed very low cytotoxicity (CC > 80 μM), thus providing a wide therapeutic window. Structural modifications provided valuable insights into structure-activity relationships and strategies for activity optimization. The hydroxy-naphthalene scaffold of 13 and 16 revealed a previously unrecognized binding site (Glu575) on the PAD4 enzyme, which was visualized through docking simulations. These inhibitors serve as valuable tools for investigating PAD functions and exploring potential therapeutic applications.

Sydney Kong

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