Optimization and Characterization of Novel Antifungal Peptides

新型抗真菌肽的优化和表征

• 批准号: 10476773
• 负责人: Kara S Keedy
• 金额: $ 30.65万
• 依托单位: AIMMAX THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10476773
• 关键词: Acids; Acute; Address; Amines; Antibiotic Resistance; Antifungal Agents; Arginine; Azoles; Basic Amino Acids; Biological Assay; Candida; Candida albicans; Candida auris; Candida glabrata; Candidiasis; Cell membrane; Cells; Centers for Disease Control and Prevention (U.S.); Chemistry; Clinical; Core Protein; Cytolysis; Data; Development; Disease; Dose; Drug Interactions; Drug Kinetics; Drug resistance; Ensure; Erythrocytes; Evaluation; Fungal Drug Resistance; Goals; HepG2; Hepatitis B Virus; High Pressure Liquid Chromatography; Human; In Vitro; Industrial fungicide; Infection; Life; Link; Mammalian Cell; Microbiology; Minimum Inhibitory Concentration measurement; Modification; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mycoses; Nature; Parents; Peptide Fragments; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Physiological; Plasma; Polyenes; Population; Prevalence; Primary carcinoma of the liver cells; Process; Property; Reporting; Resistance; Resistance development; Resistant candida; Safety; Selection Criteria; Series; Serum; Small Business Innovation Research Grant; Sodium Chloride; Solubility; Structure-Activity Relationship; Testing; Therapeutic; Time; Tissues; Toxic effect; Triazoles; United States; Work; alternative treatment; antimicrobial peptide; base; candidate selection; chemical stability; combat; cytotoxicity; design; in vitro activity; in vivo; in vivo evaluation; liquid chromatography mass spectrometry; mortality; mouse model; novel; programs; resistant strain; response; screening; transmission process

PROJECT SUMMARY / ABSTRACT Invasive candidiasis is a disease associated with significant morbidity and mortality, with only 3 classes of antifungals available for treatment. While Candida albicans remains the most common species associated with this disease, other non-albicans Candida species are emerging or growing in prevalence. The global emergence of Candida auris, a species with a high rate of multi-drug resistance capable of nosocomial transmission, and reports of Candida glabrata infections resistant to both azoles and echinocandins, highlight the critical need for new classes of antifungal drugs that can combat resistance and treat invasive fungal diseases. AimMax Therapeutics is developing a novel class of promising antifungal peptides that are differentiated from other antimicrobial peptides in development. Peptides have been considered as promising therapeutics because of their novel mechanisms of action, rapid cidality, low propensity for resistance development and low potential for drug-drug interactions. However, there are certain liabilities associated with historical antimicrobial peptides as systemic therapeutics, including propensity for lysis of human cell membranes causing toxicity and degradation by circulating proteases and peptidases. Our preliminary studies have shown that: 1) several of the AimMax peptides have antifungal activity across Candida species, including activity against resistant strains, 2) this activity is rapidly fungicidal in nature, 3) there is no cell lysis or intracellular cytotoxicity against human cells and they are well-tolerated following repeat dosing in vivo, 4) they are salt tolerant and retain activity under physiological conditions, and 5) they can be modified to increase stability against proteolytic degradation and demonstrate good plasma exposure in vivo. The objective of this proposal is to optimize the peptides by enhancing antifungal activity and microbiological profile, while maintaining safety (no toxicity) and minimizing proteolytic instability and undesirable physicochemical properties. These studies are essential to select potent antifungal peptides to combat resistance and ensure that they are “druggable” for further development. The objectives of the proposal will be achieved by rational peptide design and structure-activity relationship analysis using data from a series of in vitro and in vivo screening assessments. Peptides selected based on pre-determined criteria will undergo expanded evaluations. Together, these studies will form the basis of candidate selection for further development and IND-enabling work in a Phase 2 SBIR application. The ultimate goal of this program is to develop a broad- spectrum antifungal drug that will address the rising threat of drug resistance in Candida species and provide an alternative treatment option for life-threatening invasive candidiasis.

项目概要/摘要 侵袭性念珠菌病是一种具有显着发病率和死亡率的疾病，只有 3 类 抗真菌药物可用于治疗，而白色念珠菌仍然是与真菌相关的最常见物种。 在这种疾病中，其他非白色念珠菌属物种正在全球出现或流行。 耳念珠菌（Candida auris）的出现，这是一种具有高度多重耐药性的物种，能够在医院内传播 传播以及对唑类和棘白菌素耐药的光滑念珠菌感染的报告，强调 迫切需要能够对抗耐药性和治疗侵袭性真菌的新型抗真菌药物 AimMax Therapeutics 正在开发一类有前景的新型抗真菌肽。 与正在开发的其他抗菌肽不同，被认为是有前途的。 因其作用机制新颖、杀灭速度快、耐药倾向低而成为治疗药物 然而，存在与药物相互作用相关的某些责任。 历史上抗菌肽作为治疗系统，包括溶解人体细胞的倾向 我们的初步研究表明，膜通过循环蛋白酶和肽酶引起毒性和降解。 已经表明：1) 几种 AimMax 肽对念珠菌属物种具有抗真菌活性，包括 针对抗性菌株的活性，2) 这种活性本质上是快速杀真菌，3) 没有细胞裂解或 对人体细胞具有细胞内细胞毒性，并且在体内重复给药后具有良好的耐受性，4) 具有耐盐性并在生理条件下保留活性，并且 5) 它们可以被修饰以增加 对抗蛋白水解降解的稳定性并在体内表现出良好的血浆暴露。 建议通过增强抗真菌活性和微生物特征来优化肽，同时 保持安全（无毒性）并最大限度地减少蛋白水解不稳定性和不良理化 这些研究对于选择有效的抗真菌肽来对抗耐药性并确保其具有至关重要的作用。 该提案的目标将通过合理的方式实现。 使用一系列体外和体内数据进行肽设计和结构-活性关系分析 根据预先确定的标准选择的肽将进行扩大的筛选评估。 这些研究将共同​​构成进一步发展和选择候选人的基础。 第二阶段 SBIR 应用中的 IND 支持工作 该计划的最终目标是开发一个广泛的 谱抗真菌药物，将解决念珠菌物种日益增长的耐药性威胁，并提供 危及生命的侵袭性念珠菌病的替代治疗选择。