Institute of Biomolecular Chemistry, National Research Council (CNR), Trav. La Crucca 3, 07100, Sassari, Italy.
Institute of Biomolecular Chemistry, National Research Council (CNR), Trav. La Crucca 3, 07100, Sassari, Italy.
Eur J Med Chem. 2022 Feb 5;229:114002. doi: 10.1016/j.ejmech.2021.114002. Epub 2021 Nov 18.
Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment of inflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalent inhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis and in vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitors which are able to inhibit IL-1β release in activated macrophages in the low μM range, in line with the best activities observed for the known covalent inhibitors. Our compounds could form the basis of further optimization towards potent drugs for the treatment of inflammation and inflammatory disorders including also dysregulated inflammation in Covid 19.
靶向炎症小体-半胱氨酸蛋白酶-1 途径的化合物可用于治疗炎症和炎症性疾病。以前的半胱氨酸蛋白酶-1 抑制剂绝大多数是共价抑制剂，在临床试验中失败。我们采用混合建模、计算筛选、合成和体外测试方法，鉴定出了一类新型的非共价半胱氨酸蛋白酶-1 非细胞毒性抑制剂，它们能够以低 μM 的范围抑制激活的巨噬细胞中 IL-1β 的释放，与已知的共价抑制剂观察到的最佳活性一致。我们的化合物可以作为进一步优化的基础，以开发用于治疗炎症和炎症性疾病的有效药物，包括在新冠病毒感染中失调的炎症。
