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 八胞菌素(A-D)是环状非核糖体合成的抗真菌多肽，具有 亚微摩尔杀菌剂对多种真菌的杀菌活性。生产的最优化 并从液体培养物中分离出球孢菌素。制作和制作 分离出一种主要的类似物，称为OCF001，支持其商业化 作为一种新的抗真菌疗法的开发。几个基准测试用于评估 一种新的治疗方法的开发已经在OCF001上得到了满足。OCF001是一种有效的抗真菌药物 对氟康唑和卡泊芬净耐药的念珠菌。它也被证明是有效的。 在0.25g/ml时抑制金黄色念珠菌。抗真菌药通过诱导细胞凋亡而触发细胞死亡 在酵母细胞中，并被证明在28天内给予2 mg/kg的小鼠的毒性最小 毒性研究。此外，OCF001已被证明是一种有效的抗真菌治疗方法 小鼠的阴道酵母菌感染。所有这些研究都表明，有必要进一步推动临床前研究 这种新型化合物的开发。OCF001和极少数抗真菌化合物一起，具有 符合这些标准中的任何一个，因此它有望成为一种潜在的抗真菌疗法 探员。本申请的目标是完成新药预研(Pre-IND) 开发用于治疗的抗真菌产品的使能和IND使能研究 全身和阴道酵母菌感染。