Laboratório de Biologia Celular do IOC, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
Antimicrob Agents Chemother. 2013 Sep;57(9):4151-63. doi: 10.1128/AAC.00070-13. Epub 2013 Jun 17.
Chagas disease affects more than 10 million people worldwide, and yet, as it has historically been known as a disease of the poor, it remains highly neglected. Two currently available drugs exhibit severe toxicity and low effectiveness, especially in the chronic phase, while new drug discovery has been halted for years as a result of a lack of interest from pharmaceutical companies. Although attempts to repurpose the antifungal drugs posaconazole and ravuconazole (inhibitors of fungal sterol 14α-demethylase [CYP51]) are finally in progress, development of cheaper and more efficient, preferably Trypanosoma cruzi-specific, chemotherapies would be highly advantageous. We have recently reported that the experimental T. cruzi CYP51 inhibitor VNI cures with 100% survival and 100% parasitological clearance both acute and chronic murine infections with the Tulahuen strain of T. cruzi. In this work, we further explored the potential of VNI by assaying nitro-derivative-resistant T. cruzi strains, Y and Colombiana, in highly stringent protocols of acute infection. The data show high antiparasitic efficacy of VNI and its derivative (VNI/VNF) against both forms of T. cruzi that are relevant for mammalian host infection (bloodstream and amastigotes), with the in vivo potency, at 25 mg/kg twice a day (b.i.d.), similar to that of benznidazole (100 mg/kg/day). Transmission electron microscopy and reverse mutation tests were performed to explore cellular ultrastructural and mutagenic aspects of VNI, respectively. No mutagenic potential could be seen by the Ames test at up to 3.5 μM, and the main ultrastructural damage induced by VNI in T. cruzi was related to Golgi apparatus and endoplasmic reticulum organization, with membrane blebs presenting an autophagic phenotype. Thus, these preliminary studies confirm VNI as a very promising trypanocidal drug candidate for Chagas disease therapy.
恰加斯病影响着全球超过 1000 万人，然而，由于它在历史上被认为是一种穷人的疾病，因此仍然被高度忽视。目前有两种可用的药物具有严重的毒性和低疗效，特别是在慢性期，而由于制药公司缺乏兴趣，新药研发已经停滞多年。尽管尝试重新利用抗真菌药物泊沙康唑和拉夫康唑（真菌固醇 14α-脱甲基酶[CYP51]抑制剂）终于在进行中，但开发更便宜、更有效的、最好是针对克氏锥虫特异性的化疗药物将是非常有利的。我们最近报道称，实验性克氏锥虫 CYP51 抑制剂 VNI 以 100%的存活率和 100%的寄生虫清除率治愈了 Tulahuen 株克氏锥虫的急性和慢性小鼠感染。在这项工作中，我们通过在高度严格的急性感染方案中检测硝基衍生物抗性的克氏锥虫菌株 Y 和 Colombiana，进一步探索了 VNI 的潜力。数据显示，VNI 及其衍生物（VNI/VNF）对与哺乳动物宿主感染（血流和阿米巴）相关的两种形式的克氏锥虫均具有很高的抗寄生虫功效，其体内效力与苯并咪唑（100mg/kg/天）相当。进行了透射电子显微镜和反向突变试验，分别探索了 VNI 的细胞超微结构和诱变方面。在高达 3.5 μM 的范围内，Ames 试验未显示出诱变潜力，而 VNI 对克氏锥虫诱导的主要超微结构损伤与高尔基体和内质网组织有关，膜泡呈现自噬表型。因此，这些初步研究证实 VNI 是一种非常有前途的治疗恰加斯病的杀锥虫药物候选物。
