Department of Pharmaceutical Sciences, College of Pharmacy , The University of Jordan , Amman 11942 , Jordan.
J Med Chem. 2019 Oct 24;62(20):9026-9044. doi: 10.1021/acs.jmedchem.9b00294. Epub 2019 Oct 4.
Gallinamide A, originally isolated with a modest antimalarial activity, was subsequently reisolated and characterized as a potent, selective, and irreversible inhibitor of the human cysteine protease cathepsin L. Molecular docking identified potential modifications to improve binding, which were synthesized as a suite of analogs. Resultingly, this current study produced the most potent gallinamide analog yet tested against cathepsin L (, = 0.0937 ± 0.01 nM and / = 8 730 000). From a protein structure and substrate preference perspective, cruzain, an essential cysteine protease, is highly homologous. Our investigations revealed that gallinamide and its analogs potently inhibit cruzain and are exquisitely toxic toward in the intracellular amastigote stage. The most active compound, , had an IC = 5.1 ± 1.4 nM, but was relatively inactive to both the epimastigote (insect stage) and the host cell, and thus represents a new candidate for the treatment of Chagas disease.
鸽纳酰胺 A 最初被分离出来时具有中等的抗疟活性，随后被重新分离并鉴定为一种有效的、选择性的、不可逆的人半胱氨酸蛋白酶 cathepsin L 抑制剂。分子对接确定了潜在的修饰方法来提高结合能力，这些修饰方法被合成为一系列类似物。因此，这项当前的研究产生了迄今为止针对 cathepsin L 测试的最有效的鸽纳酰胺类似物（Ki 值为 0.0937 ± 0.01 nM，抑制常数 Ki 值为 8730000）。从蛋白质结构和底物偏好的角度来看，crurazain 是一种重要的半胱氨酸蛋白酶，与它高度同源。我们的研究表明，鸽纳酰胺及其类似物能够强烈抑制 cruzain，并对细胞内无鞭毛体阶段的 高度毒性。最有效的化合物 ，IC50 值为 5.1 ± 1.4 nM，但对前鞭毛体（昆虫阶段）和宿主细胞的活性相对较低，因此代表了一种治疗恰加斯病的新候选药物。
