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.

项目摘要在戴着隐形眼镜的健康个体中，可以发生Acanthamoeba角膜炎（AK），这是一种痛苦的盲目由自由活动的阿米巴·阿斯塔梅巴（Ameba Acanthamoeba）引起的角膜感染。并发症包括慢性眼炎症，角膜融化和疤痕。当前对AK的治疗依赖于洗具甲啶的组合，丙酰胺等环酸盐和聚甲基甲基二圭酰胺。但是，在10％的情况下，复发感染随之而来的是，由于难以杀死滋养体和双壁囊肿。因此，发展高效且安全的药物是避免失明的至关重要的需求。因为AK是一种罕见疾病，所以药物行业和药物发现的药物发现工作很少依靠学术研究中心。降低与发展相关的成本，时间和风险新的AK疗法，我们专注于完成I/II阶段安全性的局部latrunculin B的开发，对AK治疗的眼高血压和青光眼患者的耐受性和效率研究。海洋天然产物latrunculin b，靶向A. castellanii滋养体的肌动蛋白细胞骨架，发现在表型屏幕中的amebicidal为该提案奠定了基础。与此提案有关的数据表明（1）latrunculin b是针对三种临床菌株的amegicial，（2）短暂的治疗 latrunculin b的浓度导致肌动蛋白丝的沉积和随后的混乱 Castellanii滋养体中的杏心霉菌，以及（3）PI开发的新型基于图像的囊性测定可用于研究Latrunculin B的杀性效应B。根据这些数据，我们建议1）测试 latrunculin b，针对acanthamoeba多种基因型的滋养体和囊肿，2）导致耐受性以及针对AK的额外给药的LATRUNCULIN B的药代动力学 - 药物动力学研究，3）测试由两种不同的Acanthamoeba引起的AK动物模型中局部拉隆蛋白B的体内效率基因型。这项研究是获得偏向卫生的孤儿药物设计的必要步骤 latrunculin b用于治疗AK。鉴于对Acanthamoeba验证的药物靶标的辩护，这项研究还将增强AK的新型靶向治疗选择的开发。这项工作中获得的结果可能会扩展到其他自由活动的Amebae。为了成功实现建议目标，我们依靠我们的合作结合了Acanthamoeba寄生虫生物学和博士Debnath（PI）的独特专业知识。眼科中的Afshari（共同研究器）。博士。 Debnath和Afshari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翻译水平。