We have revealed a non-canonical recognition feature that can modulate the binding kinetics of hydrocarbon stapled-peptides interactions with the eIF4E protein.
Novel Dual Inhibitors of Calpain and Lipid Peroxidation. -Four hybrid molecules consisting of a peptidic backbone of classical calpain inhibitors, a hydroxytetrahydrofuran group as a calpain pharmacophore, and a potent antioxidant part, are synthesized by a 4-step synthesis from leucine methyl ester. Calpain is very sensitive to the nature of the antioxidant part and 2-substituted phenothiazines are superior to other antioxidants in the calpain and LPO tests. Hybrid compound (Ia) is a potent inhibitor of isolated calpain as well as a powerful free radical scavenger. The prodrug of (Ia), (Ib), is superior to (Ia) in cellular assays. Hybrids are much more active in the protection against C6 glial cell death compared to Z-LL-H. -(AUVIN*, S.; PIGNOL, B.; NAVET, E.; PONS, D.; MARIN, J.-G.; BIGG, D.; CHABRIER, P.-E.; Bioorg. Med.
Cell death is a common feature observed in neurodegenerative disorders, and is often associated with calpain activation and overproduction of reactive oxygen species (ROS). This study investigated the use of calpain inhibitors and antioxidants in combination to protect cells against necrosis. Maitotoxin (MTX), which induces a massive influx of calcium, was used to provoke neuronal cell death. This toxin increased, in a concentration-dependent manner, both calpain activity and ROS formation. Calpain inhibitors or antioxidants inhibited MTX-induced necrosis only marginally (below 20%), whereas their association protected against cell death by 40-66% in a synergistic manner. BN 82204, which possesses both calpain-cathepsin L inhibitory and antioxidant properties, and its acetylated pro-drug BN 82270, totally protected cells at 100 lM. The pro-drug BN 82270, which had better cell penetration, was twice as effective as the active principle BN 82204 in protecting glioma C6 or neuroblastoma SHSY5Y cells against death. These results suggest the potential therapeutic relevance of using a single molecule with multiple activities (cysteine protease inhibitor/antioxidant), and warrant further in vivo investigations in models of neuronal disorders.
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