Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Ave., Columbus, Ohio 43210, United States.
Entrada Therapeutics, 50 Northern Avenue, Boston, Massachusetts 02210, United States.
J Med Chem. 2020 Nov 12;63(21):12853-12872. doi: 10.1021/acs.jmedchem.0c01236. Epub 2020 Oct 19.
Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease with a high morbidity and mortality rate, for which no pharmacologic treatment is currently available. Our previous studies discovered that a pivotal step in the disease process is the activation of the nuclear factor of activated T cells (NFAT) c3 in lung macrophages, suggesting that inhibitors against the upstream protein phosphatase calcineurin should be effective for prevention/treatment of ARDS. Herein, we report the development of a highly potent, cell-permeable, and metabolically stable peptidyl inhibitor, CNI103, which selectively blocks the interaction between calcineurin and NFATc3, through computational and medicinal chemistry. CNI103 specifically inhibited calcineurin signaling and and exhibited a favorable pharmacokinetic profile, broad tissue distribution following different routes of administration, and minimal toxicity. Our data indicate that CNI103 is a promising novel treatment for ARDS and other inflammatory diseases.
急性呼吸窘迫综合征（ARDS）是一种炎症性肺病，发病率和死亡率都很高，目前尚无有效的药物治疗方法。我们之前的研究发现，疾病过程中的一个关键步骤是肺巨噬细胞中活化 T 细胞的核因子（NFAT）c3 的激活，这表明针对上游蛋白磷酸酶钙调神经磷酸酶的抑制剂应该对 ARDS 的预防/治疗有效。在此，我们通过计算化学和药物化学报告了一种高度有效、细胞渗透性和代谢稳定的肽抑制剂 CNI103 的开发，该抑制剂通过选择性地阻断钙调神经磷酸酶和 NFATc3 之间的相互作用。CNI103 特异性抑制钙调神经磷酸酶信号转导，并表现出有利的药代动力学特征，在不同给药途径下具有广泛的组织分布和最小的毒性。我们的数据表明，CNI103 是治疗 ARDS 和其他炎症性疾病的一种有前途的新型治疗方法。
