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.

项目总结/摘要 侵袭性念珠菌病是一种与显著发病率和死亡率相关的疾病，仅有3类 抗真菌药物可用于治疗。虽然白色念珠菌仍然是最常见的物种与 除了这种疾病，其他非白色念珠菌属正在出现或流行。全球 耳念珠菌的出现，一种具有高比率的多重耐药性的物种，能够在医院内 传播，以及光滑念珠菌感染对唑类和棘白菌素耐药的报告，强调 迫切需要新的抗真菌药物，可以对抗耐药性和治疗侵袭性真菌 疾病AimMax Therapeutics正在开发一种新型的有前途的抗真菌肽， 与其他抗菌肽的区别。肽被认为是有前途的 由于其新颖的作用机制、快速的恢复性、低的耐药性倾向， 开发和药物相互作用的可能性低。然而，与此相关的某些负债 作为全身治疗剂历史抗微生物肽，包括人细胞裂解倾向 通过循环蛋白酶和肽酶引起毒性和降解的膜。我们的初步研究 已经表明：1）几种AimMax肽在念珠菌属物种中具有抗真菌活性，包括 对抗性菌株的活性，2）该活性在性质上是快速杀真菌的，3）没有细胞裂解或 它们具有针对人细胞的细胞内细胞毒性，并且它们在体内重复给药后耐受良好，4）它们 是耐盐的，并且在生理条件下保持活性，和5）它们可以被修饰以增加 抗蛋白水解降解稳定性，并在体内显示出良好的血浆暴露。的目的 建议是通过增强抗真菌活性和微生物特性来优化肽， 保持安全性（无毒性）并使蛋白水解不稳定性和不希望的物理化学性质最小化 特性.这些研究对于选择有效的抗真菌肽来对抗耐药性并确保 它们是“可药物化的”以进一步发展。提案的目标将通过合理的 肽设计和结构活性关系分析，使用来自一系列体外和体内的数据 筛选评估。基于预先确定的标准选择的肽将进行扩增。 评价。这些研究将共同构成进一步发展的候选人选择的基础， 第2阶段SBIR应用中的IND启用工作。该计划的最终目标是建立一个广泛的- 一种广谱抗真菌药物，将解决念珠菌耐药性日益严重的威胁，并提供 一种治疗危及生命的侵袭性念珠菌病的替代治疗方案。