MICA: Pre-Clinical Development of a Small Molecule anti-Wolbachia Candidate Macrofilaricide Drug

MICA：小分子抗沃尔巴克氏体候选杀大丝虫药物的临床前开发

• 批准号: MR/R025401/1
• 负责人: Stephen Ward
• 金额: $ 189.94万
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR025401%2F1
• 关键词: MICA; Pre; Clinical; Development; Small

Lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness) are two important neglected tropical diseases that cause severe disability and affect more than 157 million people globally. Control efforts are hindered by the lack of a safe macrofilaricidal (adult parasite killing) drug. Targeting the Wolbachia bacterial endosymbionts in these parasites with doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. As part of an ongoing macrofilaricide drug discovery project we have successfully completed a lead optimisation programme to deliver a pre-clinical candidate anti-Wolbachia based macrofilaricide. The candidate AWZ1066S shows superior efficacy compared to doxycycline in a range of validated animal infection models, meets all current Target Candidate Profile characteristics (including extensive non-GLP safety/pharmacology and DMPK evaluation) and is positioned for onward development. We now request funding to support the critical formal pre-clinical development programme in order to progress AWZ1066S to the first into man transition.

淋巴丝虫病（象皮病）和盘尾丝虫病（河盲症）是两种被忽视的重要热带疾病，它们造成严重残疾，影响全球1.57亿多人。由于缺乏一种安全的杀灭大型丝虫（成虫寄生虫）药物，控制工作受到阻碍。用多西环素靶向这些寄生虫中的Wolbachia细菌内共生体导致杀巨丝虫的结果，但长期的治疗方案和禁忌症限制了其广泛实施。作为正在进行的杀微丝蚴剂药物发现项目的一部分，我们成功完成了一项先导优化计划，以提供一种基于抗沃尔巴克氏体的杀微丝蚴剂的临床前候选药物。在一系列经验证的动物感染模型中，候选药物AWZ 1066 S显示出比多西环素更优的上级疗效，符合所有当前目标候选药物特征（包括广泛的非GLP安全性/药理学和DMPK评价），并可用于进一步开发。我们现在申请资金支持关键的正式临床前开发项目，以将AWZ 1066 S进展为首次向人体转化。

项目成果

Transformation of the Manufacturing Process from Discovery to Kilogram Scale for AWZ1066S: A Highly Specific Anti- Wolbachia Drug Candidate for a Short-Course Treatment of Filariasis

AWZ1066S 的制造工艺从发现到公斤级的转变：用于短期治疗丝虫病的高度特异性抗沃尔巴克氏体候选药物

• DOI: 10.1021/acs.oprd.2c00167
• 发表时间: 2023
• 期刊: Organic Process Research & Development
• 影响因子: 3.4
• 作者: Hong W

Combinations of the azaquinazoline anti-Wolbachia agent, AWZ1066S, with benzimidazole anthelmintics synergise to mediate sub-seven-day sterilising and curative efficacies in experimental models of filariasis

• DOI: 10.3389/fmicb.2024.1346068
• 发表时间: 2024-02-01
• 期刊: FRONTIERS IN MICROBIOLOGY
• 影响因子: 5.2
• 作者: Hegde，Shrilakshmi;Marriott，Amy E.;Turner，Joseph D.
• 通讯作者: Turner，Joseph D.