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.

项目摘要/摘要 侵袭性念珠菌病是一种与显著的发病率和死亡率相关的疾病，仅有3类 可供治疗的抗真菌药物。而白色念珠菌仍然是与 除了这种疾病，其他非白念珠菌物种正在出现或流行。《环球报》 医院内多重耐药率高的金黄色念珠菌的出现 传播，以及对唑类和棘球菌素均耐药的光滑假丝酵母菌感染的报告，重点 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 疾病。AimMax治疗公司正在开发一种新的有希望的抗真菌多肽，这些多肽 在开发中区别于其他抗菌肽。多肽一直被认为是很有前途的 治疗药物，因为其作用机制新颖，杀灭迅速，耐药倾向低 发展和药物与药物相互作用的低潜力。然而，存在与以下方面相关的某些责任 抗菌肽作为系统疗法的历史，包括对人类细胞的溶解倾向 通过循环中的蛋白水解酶和肽酶引起毒性和降解的膜。我们的初步研究 研究表明：1)几种AimMax多肽在假丝酵母菌中具有抗真菌活性，包括 对耐药菌株的活性，2)这种活性在性质上是快速杀菌的，3)没有细胞裂解或 对人体细胞的细胞内毒性，在体内重复给药后耐受性良好，4)它们 耐盐并在生理条件下保持活性，以及5)它们可以被修改以增加 对蛋白质降解的稳定性，并在体内表现出良好的血浆暴露。这样做的目的是 建议通过增强抗真菌活性和微生物图谱来优化多肽，而 保持安全(无毒)，最大限度地减少蛋白质分解的不稳定性和不受欢迎的物理化学 属性。这些研究对于选择有效的抗真菌多肽来对抗耐药性和确保 他们是“可下药的”，可以进一步发展。提案的目标将通过理性的方式实现 利用一系列体内外数据进行多肽设计和构效关系分析 筛选评估。根据预先确定的标准选择的多肽将进行扩展 评估。总之，这些研究将成为进一步发展和选择候选人的基础 在阶段2 SBIR应用程序中启用IND。这项计划的最终目标是发展一个广泛的- 光谱抗真菌药物，将解决假丝酵母菌不断增加的耐药性威胁，并提供 威胁生命的侵袭性念珠菌病的替代治疗选择。