New Drug Leads for Resistant Visceral Leishmaniasis

治疗耐药内脏利什曼病的新药先导物

基本信息

批准号：
10056736
负责人：
BABU L TEKWANI
金额：
$ 31.89万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-11 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056736
关键词：
Adopted Affect Amphotericin B Animals Artemisinins Back Biological Assay Biological Availability Cells Characteristics Chemicals Clinical Contracts Cutaneous Leishmaniasis Developing Countries Disease Dose Drug Kinetics Drug or chemical Tissue Distribution Drug resistance Emulsions Evaluation Excretory function Exposure to Follow-Up Studies Formulation Goals Half-Life Hour Image Analysis In Vitro Inbred BALB C Mice Laboratories Lead Left Leishmania Leishmania donovani Leishmaniasis Link Mammalian Cell Medical Metabolic Metabolism Methods Modeling Mucocutaneous leishmaniasis Multi-Drug Resistance Mus Oral Oximes Parasites Parents Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacotherapy Physiological Plasma Population Property Proteins Rattus Reporter Resistance Risk Rodent Sodium Solubility Structure Testing Therapeutic Toxic effect Transgenic Organisms Visceral Leishmaniasis absorption analog artesunate clinically relevant cost effective cytotoxicity digital imaging dimer efficacy evaluation efficacy study follow-up functional group global health improved in vivo mouse model neglected tropical diseases novel novel strategies novel therapeutics pathogen pharmacokinetics and pharmacodynamics pharmacophore pre-clinical preclinical development resistant strain response screening stability testing treatment choice

项目摘要

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.

利什曼病是一个重大的全球健康问题，全球确诊病例超过 1200 万例，每年新增约 200 万例，超过 3.5 亿人面临感染该疾病的风险。内脏利什曼病 (VL) 是最严重的疾病，如果不及时治疗通常会致命。目前的治疗选择非常有限，要么具有严重的毒性，要么由于对几乎所有临床使用的抗利什曼病药物产生耐药性而变得无效。最近的研究已鉴定出新型三环内过氧化物二聚体类似物，对杜氏利什曼原虫胞内无鞭毛体（VL 的临床相关寄生虫阶段）具有出色的抗利什曼原虫活性。与目前临床使用的抗利什曼病药物相比，这些二聚体的抗利什曼病活性好几倍。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，已显示出中等的抗利什曼原虫活性，表明其具有选择性杀利什曼原虫特性和潜在的新型作用方式。在最近的动物试验和小鼠模型的药代动力学研究中，其中一种二聚体类似物也显示出显着的口服生物利用度。因此，这些三环内过氧化物二聚体代表了有前途的新先导化合物，可以进一步优化并开发为耐药 VL 的口服治疗方法。将采用新开发的寄生虫拯救和转化测定法，对一系列具有不同连接基团的三环内过氧化物二聚体进行体外评估，以对抗杜氏乳杆菌耐药菌株的细胞内无鞭毛体阶段。这些类似物将同时针对哺乳动物细胞进行细胞毒性测试并确定选择性。寄生虫拯救和转化测定区分测试化合物的杀利什曼病和静态作用。先导类似物将进一步针对转基因杜氏乳杆菌菌株进行体内评估，以治愈 BALB/c 小鼠的 VL，体内生物利用度/药代动力学。该项目将满足治疗 VL 耐药病例的未满足的药物医疗需求，VL 是一个重要的全球健康问题。