New Drug Leads for Resistant Visceral Leishmaniasis

利什曼病是一个重大的全球健康问题，全世界有超过1200万确诊病例，每年新增约200万例，超过3.5亿人面临接触这种疾病的风险。内脏利什曼病(VL)是这种疾病最严重的形式，如果不治疗，往往是致命的。目前的治疗选择非常有限，遭受严重毒性，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。最近的研究已经发现了新的三环内过氧化二聚体类似物，它们对临床上与VL相关的寄生虫杜氏利什曼原虫的胞内无鞭毛体具有显著的抗利什曼活性。与目前临床使用的抗利什曼药物相比，这些二聚体的抗利什曼活性要好几倍。青蒿素和青蒿琥酯是新型三环内过氧化二聚体的母药，显示出中等的抗利什曼活性，表明具有选择性的利什曼杀菌特性和潜在的新作用模式。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，这些三环内过氧化二聚体代表着很有希望的新线索，可以进一步优化和开发，作为口服治疗耐药VL的药物。一组具有不同连接基的三环内过氧化二聚体将采用新开发的寄生虫拯救和转化试验，在体外对杜氏乳杆菌耐药株的无鞭毛体阶段进行评估。这些类似物将同时针对哺乳动物细胞进行细胞毒性和选择性测定。寄生虫解救和转化试验区分了受试化合物的杀利什曼和静态作用。该铅类似物可用于进一步评价转基因杜诺瓦尼乳杆菌在BALB/c小鼠体内治疗VL的疗效、体内生物利用度/药代动力学。该项目将满足治疗VL耐药病例的未得到满足的医疗需求，VL是一个重要的全球健康问题。

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.