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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要棘阿米巴角膜炎 (AK) 可能发生在戴隐形眼镜的健康人身上，这是一种痛苦的致盲性疾病由自由生活的阿米巴棘阿米巴引起的角膜感染并发症包括慢性眼部疾病。目前 AK 的治疗依赖于氯己定、然而，10%的病例会出现复发性感染。由于难以杀死滋养体和双壁包囊，因此发生了发育。有效和安全的药物是避免失明的一个关键的未得到满足的需求，因为 AK 是一种罕见的疾病，所以存在一个关键的未满足的需求。制药行业缺乏药物发现工作，而针对这种感染的药物发现很大程度上依靠学术研究中心来减少与开发相关的成本、时间和风险。新的 AK 疗法，我们专注于开发已完成 I/II 期安全性的外用 latrunculin B，高眼压症和青光眼患者对 AK 治疗的耐受性和疗效研究。海洋天然产物 latrunculin B，其靶向 A.castellanii 滋养体的肌动蛋白细胞骨架，并发现表型筛选中的阿米巴杀灭剂，为该提案奠定了基础与该提案相关的数据表明。 (1) latrunculin B 对 A.castellanii 的三种临床菌株具有杀阿米巴作用，(2) 治疗时间短，治疗效果低 latrunculin B 的浓度导致肌动蛋白丝解聚并随后解体 A.castellanii 滋养体中的棘足，以及 (3) PI 开发的一种新型的基于图像的杀囊测定法可用于研究 latrunculin B 的杀囊作用。根据这些数据，我们建议 1) 测试 latrunculin B，对抗棘阿米巴多种基因型的滋养体和包囊，2) 行为耐受性局部施用 latrunculin B 进行 AK 的药代动力学-药效学研究，以及 3) 测试局部 latrunculin B 在两种不同棘阿米巴引起的 AK 动物模型中的体内疗效这项研究是获得局部给药孤儿药资格的必要步骤。鉴于棘阿米巴经验证的药物靶标存在缺陷，本研究采用 latrunculin B 治疗 AK。还将促进 AK 新型靶向治疗方案的开发。可能会扩展到其他自由生活的阿米巴虫，为了成功实现提案目标，我们依靠我们的。该合作结合了 Debnath 博士（PI）在棘阿米巴寄生虫生物学方面的独特专业知识和 Dr. Afshari 在眼科领域（共同研究员）。 Debnath 和 Afshari 博士的专业知识和经验具有潜力。将我们的药物发现平台提升到转化水平。