Duschak Vilma G
Instituto Nacional de Parasitología Dr. Mario Fatala Chaben, ANLIS-Malbrán, Ministerio de Salud de la nación. Av. Paseo Colon 568 (1063), Buenos Aires, Argentina.
Recent Pat Antiinfect Drug Discov. 2011 Sep 1;6(3):216-59. doi: 10.2174/157489111796887864.
Chagas disease, a parasitic infection typically spread by triatomine bugs, affects millions of people throughout Latin America. Current chemotherapy based on the nitroaromatic compounds, benzonidazole and nifurtimox provides unsatisfactory results and suffers from considerable side effects. Therefore, there is still an urgent need for new drugs to treat this neglected disease. During the last decade, the advances and understanding in the biology and biochemistry of Trypanosoma cruzi have allowed the identification of multiple new targets for Chagas' disease chemotherapy. Among the most promising targets for antiparasitic drugs are: cruzipain, the main cysteine protease of T. cruzi, essential for parasite survival and proliferation in mammalian host; ergosterol biosynthesis pathway; trypanothione synthesis and thiol-dependant redox metabolism. Specific enzymes of the glycolytic, pentose phosphate, polyisoprenoid (farnesylpyrophosphate synthase) and other particular biosynthetic pathways as well as enzymes from purine salvage (hypoxanthine-guanine phosphoribosyl-transferase, dihydrofolate reductase) have also been intensively studied in T. cruzi. In particular, trypanocidal agents that target the validated biochemical pathways of the parasite including cysteine proteinase inhibitors and inhibitors capable to block ergosterol biosynthesis are currently in the pipeline. Among the latter, posaconazole and ravuconazole, are planned to enter in clinical trials for trypanocidal chemotherapy in the near future. This review will summarize advances on antichagasic agents directed to specific parasite targets such as metabolic pathways or specific enzymes. Related patents filed and issued from 2000 to 2010 claiming inhibitors for specific parasite targets will be also discussed. Among them, the most represented were those related with cysteine proteinase inhibitors.
恰加斯病是一种通常由锥蝽传播的寄生虫感染病，影响着拉丁美洲数百万人口。目前基于硝基芳香化合物苯并硝唑和硝呋替莫的化疗效果不尽人意，且副作用较大。因此，仍迫切需要新的药物来治疗这种被忽视的疾病。在过去十年中，对克氏锥虫生物学和生物化学的进展与认识，使得人们能够确定多个用于恰加斯病化疗的新靶点。抗寄生虫药物最有前景的靶点包括：克氏锥虫的主要半胱氨酸蛋白酶克氏锥虫蛋白酶，它对寄生虫在哺乳动物宿主中的存活和增殖至关重要；麦角固醇生物合成途径；锥虫硫醇合成及硫醇依赖性氧化还原代谢。糖酵解、磷酸戊糖、多异戊二烯（法尼基焦磷酸合酶）和其他特定生物合成途径的特定酶，以及嘌呤补救途径（次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶、二氢叶酸还原酶）的酶，也在克氏锥虫中得到了深入研究。特别是，针对该寄生虫已验证生化途径的杀锥虫剂，包括半胱氨酸蛋白酶抑制剂和能够阻断麦角固醇生物合成的抑制剂，目前正在研发中。其中，泊沙康唑和雷夫康唑计划在不久的将来进入杀锥虫化疗的临床试验。本综述将总结针对特定寄生虫靶点（如代谢途径或特定酶）的抗恰加斯病药物的进展。还将讨论2000年至2010年提交和发布的、声称针对特定寄生虫靶点的抑制剂的相关专利。其中，最具代表性的是与半胱氨酸蛋白酶抑制剂相关的专利。
