Departamento de Microbiologia Geral, Instituto de Microbiologia Prof. Paulo de Góes and Programa de Pós-Graduação em Bioquímica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Curr Med Chem. 2011;18(16):2401-19. doi: 10.2174/092986711795843182.
Mycoses are still one of the most problematic illnesses worldwide, especially affecting immunocompromised individuals. The development of novel antifungal drugs is becoming more demanding every day, since existing drugs either have too many side effects or they tend to lose effectiveness due to the resistant fungal strains. In this scenario, Candida albicans is still the main fungal pathogen isolated in hospitals. Pathogenicity results essentially from modifications of the host defense mechanisms that secondarily initiate transformations in the fungal behavior. The pathogenesis of C. albicans is multifactorial and different virulence attributes are important during the various stages of infection. Some virulence factors, like the secreted aspartic proteases (Saps), play a role in several infection stages and the inhibition of one of the many stages may contribute to the containment of the pathogen and thus should help in the treatment of disease. Therefore, Saps are potential targets for the development of novel anti-C. albicans drugs. Herein, we review the beneficial properties of pepstatin A and aspartic-type protease inhibitors used in the anti-human immunodeficiency virus chemotherapy on C. albicans, with particular emphasis in the effects on Sap activity, proliferation, morphogenesis (yeasts into mycelia transformation), ultrastructural architecture, adhesion to mammalian cells and abiotic materials, modulation of unrelated virulence factors (e.g., surface glycoconjugates, lipases and sterol), experimental candidiasis infection as well as synergistic properties when conjugated with classical antifungals. Collectively, these positive findings have stimulated the search for novel natural and/or synthetic pharmacological compounds with anti-aspartic protease properties against the human opportunistic fungus C. albicans.
真菌感染仍然是全球最具挑战性的疾病之一，尤其影响免疫功能低下的个体。由于现有药物要么副作用太多，要么由于抗真菌菌株的出现而趋于失效，因此每天都需要开发新型抗真菌药物。在这种情况下，白色念珠菌仍然是医院中分离出的主要真菌病原体。致病性主要源于宿主防御机制的改变，这些改变会导致真菌行为的转变。白色念珠菌的发病机制是多因素的，不同的毒力属性在感染的各个阶段都很重要。一些毒力因子，如分泌的天冬氨酸蛋白酶（SAPs），在几个感染阶段发挥作用，抑制其中一个阶段可能有助于控制病原体，从而有助于疾病的治疗。因此，SAPs 是开发新型抗白色念珠菌药物的潜在靶点。在此，我们综述了抗人类免疫缺陷病毒化疗中使用的胃蛋白酶抑制剂和天冬氨酸蛋白酶抑制剂对白色念珠菌的有益特性，特别强调了对 SAP 活性、增殖、形态发生（酵母转化为菌丝）、超微结构、黏附到哺乳动物细胞和非生物材料、相关毒力因子（如表面糖缀合物、脂肪酶和固醇）的调节，实验性念珠菌感染以及与经典抗真菌药物联合使用的协同作用。总的来说，这些积极的发现促使人们寻找具有抗天冬氨酸蛋白酶特性的新型天然和/或合成药理学化合物，以对抗人类机会性真菌白色念珠菌。
