Urbina Julio A
Laboratorio de Química Biológica, Centro de Bioquímica y Biofísica, Instituto Venezolano de Invstigaciones Cientifìcas, Km.11, Carretera Panamericana, Caracas 1020, Venezuela.
Curr Pharm Des. 2002;8(4):287-95. doi: 10.2174/1381612023396177.
In this article we review the current status of chemotherapeutic approaches for the specific treatment of Chagas disease or American Trypanosomiasis, as well as new rational approaches being developed as a consequence on the increased understanding of the biochemistry and physiology of its causative agent, the protozoan parasite Trypanosoma cruzi. Currently available drugs (nitrofurans and nitroimidazoles), developed empirically over three decades ago, are unsatisfactory due to frequent toxic side effects and limited efficacy, particularly in the prevalent chronic form of the disease. Furthermore, studies of their mechanism of action have shown that their antiparasitic activity is inextricably linked to mammalian host toxicity. Recent advances in this field include the demonstration that new triazole derivatives, with selective inhibitory activity on the parasite's de novo sterol biosynthesis and special pharmacokinetic properties, can induce radical parasitological cure of both acute and chronic Chagas experimental disease. These compounds are active against nitrofuran- and nitroimidazole-resistant T.cruzi strains and maintain their activity even if the hosts are immunosuppressed and are thus logical candidates for clinical trials with Chagas disease patients. Inhibitors of cruzipain, a cathepsin L-like protease responsible for the major proteolytic activity in all stages of the life cycle of the parasite, can selectively block the proliferation of T.cruzi, both in vitro and in vivo and have curative activity in murine models of acute Chagas disease; a significant effort is being devoted to their development as antiparasitic drugs. Alkyl-lysophospholipids, which selectively block phosphatidyl-choline biosynthesis in T.cruzi, are promising antiparasitic agents with good oral activity and low toxicity. Other biochemical pathways have been identified as potential chemotherapeutic targets, including hypoxanthine-guanine phosphoribosyl transferase and the enzymes involved in the synthesis and metabolism of trypanothione and inorganic pyrophosphate.
在本文中，我们综述了用于恰加斯病（又称美洲锥虫病）特异性治疗的化疗方法的现状，以及随着对其病原体——原生动物寄生虫克氏锥虫的生物化学和生理学认识的增加而正在开发的新的合理方法。目前可用的药物（硝基呋喃类和硝基咪唑类）是三十多年前凭经验开发的，由于频繁的毒副作用和有限的疗效，尤其是在该疾病普遍存在的慢性形式中，并不令人满意。此外，对其作用机制的研究表明，它们的抗寄生虫活性与哺乳动物宿主毒性紧密相连。该领域的最新进展包括证明新的三唑衍生物对寄生虫的从头固醇生物合成具有选择性抑制活性，并具有特殊的药代动力学特性，可在急性和慢性恰加斯实验性疾病中诱导彻底的寄生虫学治愈。这些化合物对耐硝基呋喃和硝基咪唑的克氏锥虫菌株具有活性，即使宿主免疫抑制也能保持其活性，因此是恰加斯病患者临床试验的合理候选药物。克氏锥虫组织蛋白酶（一种组织蛋白酶L样蛋白酶，负责寄生虫生命周期所有阶段的主要蛋白水解活性）抑制剂可在体外和体内选择性地阻断克氏锥虫的增殖，并在急性恰加斯病小鼠模型中具有治愈活性；目前正在大力致力于将其开发为抗寄生虫药物。烷基溶血磷脂可选择性地阻断克氏锥虫中的磷脂酰胆碱生物合成，是有前景的抗寄生虫药物，具有良好的口服活性和低毒性。其他生化途径已被确定为潜在的化疗靶点，包括次黄嘌呤 - 鸟嘌呤磷酸核糖基转移酶以及参与锥虫硫醇和无机焦磷酸合成与代谢的酶。
