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; 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.

项目摘要 /摘要 侵入性念珠菌病是一种与显着发病率和死亡率相关的疾病，只有3类 可用于治疗的抗真菌。虽然白色念珠菌仍然是与 这种疾病，其他非阿尔比亚念珠菌种类正在出现或增长。全球 念珠菌的出现，一种具有高毒性耐药性速度的物种 传播和念珠菌感染对偶氮和echinocandins具有抗药性的报道，突出显示 对可以打击抗药性和治疗侵入性真菌的新类抗真菌药物的新类别的临界需求 疾病。 Aimmax Therapeutics正在开发一种新颖的承诺抗真菌胡椒粉 与其他抗菌胡椒的发育中有区别。肽被认为是有前途的 治疗学是由于其新颖的作用机理，快速文明，抵抗力低的倾向 开发和药物相互作用的潜力低。但是，与 历史抗菌胡椒作为全身疗法，包括人类细胞裂解的倾向 通过循环蛋白酶和petidass引起毒性和降解的膜。我们的初步研究 已经表明：1）几个Aimmax Pepperides在念珠菌中具有抗真菌活性，包括 抗抗性菌株的活性，2）本质本质上是迅速真菌的，3）没有细胞裂解或 对人类细胞的细胞内细胞毒性，在体内重复给药后，它们具有良好的耐受性，4） 在生理条件下是否耐盐并保留活性，5）可以修改以增加 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。这个目的 建议是通过增强抗真菌活性和微生物学特征来优化辣椒，而 保持安全性（无毒性），并最大程度地减少蛋白水解不稳定性和不良物理化学 特性。这些研究对于选择潜在的抗真菌辣椒以对抗抗药性至关重要 它们是“可毒品”的进一步发展。提案的目标将通过理性实现 肽设计和结构活性关系分析使用一系列体外和体内的数据 筛选评估。基于预定标准选择的肽将经历扩展 评估。这些研究将构成候选人选择进一步发展的基础，并 在第2阶段SBIR应用程序中的成分工作。该计划的最终目标是开发广泛的 光谱抗真菌药物将解决念珠菌中耐药性威胁的上升并提供 威胁生命的侵入性念珠菌病的另一种治疗选择。