Reguera R M, Redondo C M, Gutierrez de Prado R, Pérez-Pertejo Y, Balaña-Fouce R
Dpto. Farmacología y Toxicología (INTOXCAL), Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
Biochim Biophys Acta. 2006 Mar-Apr;1759(3-4):117-31. doi: 10.1016/j.bbaexp.2006.03.006. Epub 2006 Apr 26.
The growing occurrence of drug resistant strains of unicellular prokaryotic parasites, along with insecticide-resistant vectors, are the factors contributing to the increased prevalence of tropical diseases in underdeveloped and developing countries, where they are endemic. Malaria, cryptosporidiosis, African and American trypanosomiasis and leishmaniasis threaten human beings, both for the high mortality rates involved and the economic loss resulting from morbidity. Due to the fact that effective immunoprophylaxis is not available at present; preventive sanitary measures and pharmacological approaches are the only sources to control the undesirable effects of such diseases. Current anti-parasitic chemotherapy is expensive, has undesirable side effects or, in many patients, is only marginally effective. Under this point of view molecular biology techniques and drug discovery must walk together in order to find new targets for chemotherapy intervention. The identification of DNA topoisomerases as a promising drug target is based on the clinical success of camptothecin derivatives as anticancer agents. The recent detection of substantial differences between trypanosome and leishmania DNA topoisomerase IB with respect to their homologues in mammals has provided a new lead in the study of the structural determinants that can be effectively targeted. The present report is an up to date review of the new findings on type IB DNA topoisomerase in unicellular parasites and the role of these enzymes as targets for therapeutic agents.
单细胞原核寄生虫耐药菌株的不断出现，以及抗杀虫剂病媒，是导致热带疾病在其为地方病的欠发达国家和发展中国家患病率上升的因素。疟疾、隐孢子虫病、非洲锥虫病、美洲锥虫病和利什曼病对人类构成威胁，这既是因为涉及高死亡率，也是因为发病导致经济损失。由于目前尚无有效的免疫预防措施，预防性卫生措施和药理学方法是控制此类疾病不良影响的唯一手段。当前的抗寄生虫化疗费用高昂，有不良副作用，或者在许多患者中效果甚微。从这一角度来看，分子生物学技术和药物研发必须协同并进，以便找到化疗干预的新靶点。将DNA拓扑异构酶鉴定为有前景的药物靶点是基于喜树碱衍生物作为抗癌药物的临床成功。最近发现锥虫和利什曼原虫的DNA拓扑异构酶IB与其哺乳动物同源物之间存在显著差异，这为研究可有效靶向的结构决定因素提供了新线索。本报告是对单细胞寄生虫中IB型DNA拓扑异构酶新发现以及这些酶作为治疗药物靶点的作用的最新综述。
