Brinen L S, Hansell E, Cheng J, Roush W R, McKerrow J H, Fletterick R J
Department of Pathology, University of California, San Francisco 94143, USA.
Structure. 2000 Aug 15;8(8):831-40. doi: 10.1016/s0969-2126(00)00173-8.
Cysteine proteases of the papain superfamily are present in nearly all groups of eukaryotes and play vital roles in a wide range of biological processes and diseases, including antigen and hormone processing, bacterial infection, arthritis, osteoporosis, Alzheimer's disease and cancer-cell invasion. Because they are critical to the life-cycle progression of many pathogenic protozoa, they represent potential targets for selective inhibitors. Chagas' disease, the leading cause of death due to heart disease in Latin American countries, is transmitted by Trypanosoma cruzi. Cruzain is the major cysteine protease of T cruzi and has been the target of extensive structure-based drug design.
High-resolution crystal structures of cruzain bound to a series of potent phenyl-containing vinyl-sulfone, sulfonate and sulfonamide inhibitors have been determined. The structures show a consistent mode of interaction for this family of inhibitors based on a covalent Michael addition formed at the enzyme's active-site cysteine, hydrophobic interactions in the S2 substrate-binding pocket and a strong constellation of hydrogen bonding in the S1' region.
The series of vinyl-sulfone-based inhibitors examined in complex with cruzain was designed to probe recognition and binding potential of an aromatic-rich region of the enzyme. Analysis of the interactions formed shows that aromatic interactions play a less significant role, whereas the strength and importance of hydrogen bonding in the conformation adopted by the inhibitor upon binding to the enzyme was highlighted. A derivative of one inhibitor examined is currently under development as a therapeutic agent against Chagas' disease.
木瓜蛋白酶超家族的半胱氨酸蛋白酶几乎存在于所有真核生物群体中，并在广泛的生物过程和疾病中发挥重要作用，包括抗原和激素加工、细菌感染、关节炎、骨质疏松症、阿尔茨海默病和癌细胞侵袭。由于它们对许多致病原生动物的生命周期进展至关重要，因此它们是选择性抑制剂的潜在靶点。恰加斯病是拉丁美洲国家心脏病导致死亡的主要原因，由克氏锥虫传播。克氏锥虫半胱氨酸蛋白酶是克氏锥虫的主要半胱氨酸蛋白酶，一直是基于结构的广泛药物设计的靶点。
已确定克氏锥虫半胱氨酸蛋白酶与一系列强效含苯基乙烯基砜、磺酸盐和磺酰胺抑制剂结合的高分辨率晶体结构。这些结构显示了该家族抑制剂基于在酶活性位点半胱氨酸处形成的共价迈克尔加成、S2底物结合口袋中的疏水相互作用以及S1'区域中强大的氢键组合的一致相互作用模式。
与克氏锥虫半胱氨酸蛋白酶复合研究的一系列基于乙烯基砜的抑制剂旨在探测该酶富含芳香族区域的识别和结合潜力。对形成的相互作用的分析表明，芳香族相互作用的作用较小，而抑制剂与酶结合时所采用构象中氢键的强度和重要性得到了突出。所研究的一种抑制剂的衍生物目前正在作为治疗恰加斯病的药物进行开发。
