Latrunculin B as a new drug lead for the treatment of Acanthamoeba keratitis

Latrunculin B 作为治疗棘阿米巴角膜炎的新药先导物

• 批准号: 10192287
• 负责人: Anjan Debnath
• 金额: $ 23.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192287
• 关键词: Acanthameba infection; Acanthamoeba; Acanthamoeba Keratitis; Actins; Age; Amoeba genus; Animal Model; Biological Assay; Biology; Blindness; C57BL/6 Mouse; Chlorhexidine; Chronic; Cicatrix; Clinical; Collaborations; Contact Lenses; Cornea; Cyst; Cytoskeleton; Data; Development; Dose; Drug Industry; Drug Targeting; Emerging Communicable Diseases; Exploratory/Developmental Grant; Eye Infections; Foundations; Future; Genotype; Glaucoma; Goals; Human; Image; In Vitro; Incidence; Individual; Infection; Inflammation; Interdisciplinary Study; Intervention; Invaded; Keratitis; Lead; Libraries; Medical; Methods; Microfilaments; Modeling; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Ocular Hypertension; Ophthalmology; Orphan Drugs; Outcome; Pain; Parasites; Parasitology; Patients; Phagocytosis; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Phenotype; Physiologic Intraocular Pressure; Predisposition; Prevention; Primary Open Angle Glaucoma; Process; Publishing; Rare Diseases; Regimen; Research; Research Personnel; Risk; Safety; Scientist; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Topical agent; Topical application; Translating; Work; antimicrobial; base; cell motility; clinical development; cost; depolymerization; drug development; drug discovery; druggable target; effective intervention; efficacy study; efficacy testing; experience; high risk; in vivo; in vivo evaluation; latrunculin B; marine natural product; melting; mouse model; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; polyhexamethylene biguanide; polymerization; recurrent infection; screening; small molecule inhibitor; success; targeted treatment; therapeutic target; therapy development

PROJECT SUMMARY Acanthamoeba keratitis (AK) can occur in healthy individuals wearing contact lenses and it is a painful blinding infection of the cornea caused by a free-living ameba Acanthamoeba. Complications include chronic ocular inflammation, corneal melting and scarring. Current treatment for AK relies on a combination of chlorhexidine, propamidine isethionate, and polyhexamethylene biguanide. However, in 10% of cases recurrent infection ensues, because of the difficulty in killing both trophozoites and double-walled cysts. Therefore, development of efficient and safe drugs is a critical unmet need to avert blindness. Because AK is a rare disease, there is a paucity of drug discovery efforts by the pharmaceutical industry and drug discovery for this infection largely relies on academic research centers. To reduce the cost, time and risk associated with the development of new AK therapies, we focused on the development of topical latrunculin B that completed Phase I/II safety, tolerability and efficacy study in patients with ocular hypertension and glaucoma for the treatment of AK. Marine natural product latrunculin B, which targets actin cytoskeleton of A. castellanii trophozoites and found amebicidal in a phenotypic screen, laid the foundation for this proposal. Data related to this proposal show that (1) latrunculin B is amebicidal against three clinical strains of A. castellanii, (2) a short treatment with low concentration of latrunculin B led to depolymerization of actin filaments and subsequent disorganization of acanthopodia in A. castellanii trophozoites, and (3) a novel image-based cysticidal assay developed by the PI could be used to investigate the cysticidal effect of latrunculin B. Based on these data, we propose to 1) test latrunculin B, against trophozoites and cysts of multiple genotypes of Acanthamoeba, 2) conduct tolerability and pharmacokinetic-pharmacodynamic studies of topically administered latrunculin B for AK, and 3) test in vivo efficacy of topical latrunculin B in an animal model of AK caused by Acanthamoeba of two different genotypes. This study is a necessary step toward obtaining orphan drug designation of topically administered latrunculin B for the treatment of AK. Given a deficit of the validated drug targets in Acanthamoeba, this study will also enhance the development of novel targeted treatment option for AK. The results obtained in this work may be expanded to other free-living amebae. To successfully achieve the proposal goals, we rely on our collaboration that combines the unique expertise of Dr. Debnath (PI) in Acanthamoeba parasite biology and Dr. Afshari in ophthalmology (Co-Investigator). Drs. Debnath and Afshari’s expertise and experience has potential to elevate our drug discovery platform to a translational level.

项目摘要 阿米巴角膜炎（AK）可以发生在健康的人戴隐形眼镜，这是一个痛苦的致盲 由自由生活的变形虫引起的角膜感染。并发症包括慢性眼部 炎症、角膜融化和瘢痕形成。目前对AK的治疗依赖于氯己定， 羟乙基磺酸丙脒和聚双胍。然而，10%的病例会复发感染 包囊，因为很难杀死滋养体和双壁包囊。因此，发展 有效和安全的药物是一个关键的未满足的需要，以避免失明。因为AK是一种罕见的疾病， 制药业缺乏药物发现的努力， 依赖于学术研究中心。为了减少与开发相关的成本、时间和风险， 新的AK疗法，我们专注于开发完成I/II期安全性的局部latrunculin B， 在高眼压和青光眼患者中进行的AK治疗的耐受性和有效性研究。 海洋天然产物latrunculin B，靶向A.卡氏滋养体， 在表型筛选中，为本建议奠定了基础。与该提案相关的数据显示， (1)latrunculin B对三种临床菌株的A. Castellanii，（2）低剂量短疗程 浓度的latrunculin B导致肌动蛋白丝解聚和随后的 A. castellanii滋养体，以及（3）PI开发的基于图像的新型杀囊试验 可用于研究latrunculin B的杀囊作用。基于这些数据，我们建议1）测试 latrunculin B，抗多种基因型阿米巴的滋养体和包囊，2）进行耐受性 局部给药的latrunculin B用于AK的药代动力学-药效学研究，以及3） 局部用latrunculin B在由两种不同的阿米巴原虫引起的AK动物模型中的体内功效 基因型本研究是获得局部给药孤儿药资格的必要步骤 latrunculin B治疗AK。鉴于在阿米巴中缺乏有效的药物靶点，本研究 还将促进AK的新型靶向治疗选择的开发。在这项工作中获得的结果 可以扩展到其他自由生活的阿姆斯壮。为了成功实现提案目标，我们依靠我们的 合作，结合了独特的专业知识博士Debnath（PI）在阿米巴寄生虫生物学和博士。 眼科Afshari（合作研究者）。Debnath和Afshari博士的专业知识和经验具有潜力 将我们的药物研发平台提升到转化水平。