New Drug Leads for Resistant Visceral Leishmaniasis

利什曼病是一个重大的全球卫生问题，全世界确诊病例超过1200万例，每年新增病例约200万例，有3.5亿多人面临感染该病的风险。内脏利什曼病（VL）是最严重的利什曼病，如果不及时治疗，往往会致命。目前的治疗方案非常有限，具有严重的毒性，或者由于对几乎所有临床使用的抗利什曼药物产生耐药性而变得无效。最近的研究已经鉴定出新的三环内过氧化物二聚体类似物，它们对多诺瓦利什曼原虫的细胞内无尾线虫具有出色的抗利什曼活性，这是VL的临床相关寄生虫阶段。这些二聚体的抗利什曼原虫活性比目前临床使用的抗利什曼原虫药物要好几倍。青蒿素和青蒿酸钠是新型三环内过氧化物二聚体的母体药物，显示出中等的抗利什曼原虫活性，表明选择性利什曼原虫特性和潜在的新型作用方式。其中一种二聚体类似物在最近的动物试验和小鼠模型的药代动力学研究中也显示出显著的口服生物利用度。因此，这些三环内过氧化物二聚体代表了有希望的新线索，可以进一步优化和开发作为耐药VL的口服治疗药物。采用新开发的寄生虫拯救和转化实验，对一系列具有不同连接基团的三环内过氧化物二聚体在体外对多诺瓦尼L. donovani耐药菌株胞内无梭菌阶段的影响进行了评估。这些类似物将同时在哺乳动物细胞中进行细胞毒性测试和选择性测定。寄生虫拯救和转化试验区分了试验化合物的利什曼尼杀灭和静态作用。研究人员还将进一步研究这些引物对转基因多诺瓦氏杆菌治疗BALB/c小鼠VL的体内生物利用度和药代动力学的影响。这一项目将满足对治疗VL耐药病例（一个重要的全球卫生问题）的药物尚未满足的医疗需求。

Leishmaniasis is a major global health problem with more than 12 million confirmed cases worldwide, about two million new cases being added every year and more than 350 million people at risk of being exposed to the disease. Visceral leishmaniasis (VL), the most severe form of the diseases, is often fatal if left untreated. The current options for therapies are highly limited, suffer from severe toxicities or have become ineffective due to resistance against almost all clinically-used anti-leishmanial drugs. Recent studies have led to the identification of novel tricyclic endoperoxide dimer analogs with outstanding anti-leishmanial activities against intracellular amastigotes of Leishmania donovani, the clinically-relevant parasite stages for VL. Anti-leishmanial activities of these dimers are several-fold better as compared to the current battery of clinically used anti-leishmanial drugs. Artemisinin and sodium artesunate, the parent drugs from the novel tricyclic endoperoxide dimers, have shown moderate anti-leishmanial activity, indicating selective leishmanicidal properties and a potential novel mode-of-action. One of the dimer analogs has also shown significant oral bioavailability in recent animal trials and pharmacokinetic studies in a murine model. These tricyclic endoperoxide dimers thus represent promising new leads, which can be further optimized and developed as oral treatments for drug-resistant VL. A battery of tricyclic endoperoxide dimers with various linker groups will be evaluated in vitro against intracellular amastigote stages of drug-resistant strains of L. donovani, employing newly developed parasite-rescue and transformation assay. The analogs will be simultaneously tested against a mammalian cell for cytotoxicity and determination of selectivity. The parasite- rescue and transformation assay differentiates leishmanicidal and static actions of the test compound. The lead analogs will be advanced to further evaluation against transgenic L. donovani strains in vivo for cure of VL in BALB/c mice, in vivo bioavailability/pharmacokinetics. This project will fulfill an unmet medical need of drugs for treatment of drug-resistant cases of VL, an important global health problem.