Preclinical Development of OCF001 for Treatment of Yeast Infections

OCF001治疗酵母菌感染的临床前开发

• 批准号: 9898242
• 负责人: James Leif Smith
• 金额: $ 96.55万
• 依托单位: SANO CHEMICALS, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898242
• 关键词: Address; Anti-Infective Agents; Antifungal Agents; Apoptosis; Benchmarking; Binding Proteins; Burkholderia; Candida; Candida auris; Caspofungin; Cell Cycle Kinetics; Cell Death; Cells; Chemicals; Clinical; Development; Disease; Dose; Drug Kinetics; Exposure to; Fluconazole; Formulation; Fungal Drug Resistance; Goals; Human; In Vitro; Industrial fungicide; Infection; Investigational Drugs; Investigational New Drug Application; Knowledge; Lead; Liquid substance; Maximum Tolerated Dose; Methods; Minimum Inhibitory Concentration measurement; Modeling; Mus; Mycoses; Natural Products; Patient-Focused Outcomes; Peptides; Periodicity; Pharmaceutical Preparations; Pharmacology; Preclinical Drug Development; Predisposition; Process; Production; Property; Regimen; Research; Resistance; Resistant candida; Route; Serum; Structure; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxicology; United States Food and Drug Administration; Yeasts; analog; clinical development; clinically relevant; drug candidate; efficacy study; expectation; experience; fungus; improved; in vivo; mouse model; novel; novel therapeutic intervention; novel therapeutics; pathogenic fungus; patient population; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; therapy outcome; vaginal candidiasis; yeast infection

Project Summary Occidiofungins (A-D) are cyclic nonribosomally synthesized antifungal peptides with submicromolar fungicidal activity against a broad spectrum of fungi. Optimization of the production and isolation of occidiofungins from liquid cultures has been performed. The production and isolation of predominantly one analog, called occidiofungin B (OCF001), supports its commercial development as a novel antifungal therapeutic. Several of the benchmarks used to evaluate the development of a novel therapeutic have been met with OCF001. OCF001 is a potent antifungal against fluconazole and caspofungin-resistant Candida species. It was also shown to be effective at inhibiting Candida auris at 0.25 g/ml. The antifungal triggers cell death by inducing apoptosis in yeast cells and was shown to have minimal toxicity in mice dosed with 2 mg/kg in a 28-day toxicity study. Furthermore, OCF001 was demonstrated to be an effective antifungal treatment for vaginal yeast infections in mice. All these studies point to the need to further the preclinical development of this novel compound. OCF001, along with very few antifungal compounds, have met any of these benchmarks, and therefore it holds promise as a potential antifungal therapeutic agent. The goal of this application is to complete the pre-Investigational New Drug (pre-IND) enabling and IND enabling studies for the development of an antifungal product for the treatment of systemic and vaginal yeast infections.

项目摘要 Occidiofungins（A-D）是环状非核糖体合成的抗真菌肽， 对广谱真菌具有亚微摩尔杀真菌活性。优化生产 并且已经从液体培养物中分离了球孢子菌素。生产和 分离出一种主要的类似物，称为occidiofungin B（OCF 001），支持其商业用途 作为一种新的抗真菌治疗剂的发展。用于评估 OCF 001已经满足了新型治疗剂的开发。OCF 001是一种有效的抗真菌剂 抗氟康唑和卡泊芬净耐药念珠菌。它也被证明是有效的 在0.25 μ g/ml浓度下，对耳念珠菌的抑制作用最强。抗真菌药物通过诱导细胞凋亡引发细胞死亡 在酵母细胞中，并显示在28天内以2 mg/kg剂量给药的小鼠中具有最小毒性。 毒性研究此外，OCF 001被证明是一种有效的抗真菌治疗， 小鼠阴道酵母菌感染。所有这些研究都表明需要进一步开展临床前研究 开发这种新型化合物。OCF 001，沿着很少的抗真菌化合物， 符合这些基准中的任何一个，因此它有望成为一种潜在的抗真菌治疗药物 剂本申请的目的是完成新药临床试验前申请（pre-IND） 用于开发抗真菌产品治疗的启动和IND启动研究 全身和阴道酵母菌感染