New Drug Leads for Resistant Visceral Leishmaniasis

利什曼病是一个主要的全球健康问题，全球确诊病例超过1200万例，每年新增约200万例，超过3.5亿人面临暴露于该疾病的风险。内脏利什曼病（VL）是最严重的疾病形式，如果不及时治疗，往往是致命的。目前的治疗选择非常有限，遭受严重的毒性或由于对几乎所有临床使用的抗利什曼病药物的耐药性而变得无效。最近的研究已经导致鉴定了新的三环内过氧化物二聚体类似物，其对杜氏利什曼原虫的细胞内无鞭毛体（VL的临床相关寄生虫阶段）具有突出的抗利什曼原虫活性。这些二聚体的抗利什曼原虫活性是目前临床使用的抗利什曼原虫药物的几倍。青蒿素和青蒿琥酯钠，从新的三环内过氧化物二聚体的母体药物，已显示出中度的抗利什曼原虫活性，表明选择性杀利什曼原虫的特性和潜在的新的作用模式。二聚体类似物之一在最近的动物试验和鼠模型中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前途的新的线索，可以进一步优化和开发作为耐药VL的口服治疗。将在体外评价一组具有各种连接基团的三环内过氧化物二聚体对耐药菌株L. donovani，采用新开发的寄生虫拯救和转化试验。将针对哺乳动物细胞同时测试类似物的细胞毒性和选择性测定。寄生虫拯救和转化试验区分了供试化合物的杀利什曼原虫作用和静态作用。先导类似物将进一步用于抗转基因L. donovani菌株在BALB/c小鼠中用于治愈VL的体内生物利用度/药代动力学。该项目将满足用于治疗耐药VL病例的药物的未满足的医疗需求，这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.