Development of a novel broad spectrum antifungal therapeutic targeting Glycosylphosphatidylinositol (GPI) biosynthesis and cell wall biogenesis

开发一种针对糖基磷脂酰肌醇 (GPI) 生物合成和细胞壁生物合成的新型广谱抗真菌治疗药物

• 批准号: 10759723
• 负责人: Terry Roemer
• 金额: $ 29.93万
• 依托单位: PROKARYOTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759723
• 关键词: AIDS therapy; Address; Allergic Bronchopulmonary Aspergillosis; Amphotericin B; Anabolism; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Attenuated; Azole resistance; Azoles; Binding; Biogenesis; Candida; Candida albicans; Candida auris; Candidiasis; Cell Wall; Cell surface; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Data; Development; Disseminated candidiasis; Dose; Drug Interactions; Drug Kinetics; Drug resistance; Enhancers; Eukaryota; Evaluation; Formulation; Glycosylphosphatidylinositols; Goals; Growth; HIV/AIDS; HepG2; Human; Immune system; In Vitro; Infection; Ion Channel; Lead; Lethal Dose 50; Life; Mediating; Medicine; Metabolic; Modeling; Molds; Morbidity - disease rate; Multi-Drug Resistance; Multiple Fungal Drug Resistance; Mus; Mycoses; Names; Natural Products; Organ Transplantation; Pathway interactions; Pharmaceutical Preparations; Phase; Phenotype; Post-Translational Protein Processing; Premature Infant; Production; Property; Proteins; Publishing; Reporting; Resistance; Resistant candida; Sepsis; Series; Serum; Systemic infection; Testing; Therapeutic; Therapeutic Index; Toxic effect; Virulence; Vulnerable Populations; World Health Organization; Yeasts; analog; candidate selection; clinical development; clinically relevant; cytotoxicity; echinocandin resistance; genome-wide; health care settings; improved; in vivo; inhibitor; innovation; lead optimization; mortality; mouse model; novel; novel therapeutics; pathogen; pathogenic fungus; phase 3 study; pre-clinical; priority pathogen; programs; resistant Aspergillus; scale up; screening; standard of care; synergism; targeted treatment; therapeutic target

Widespread azole resistance among Candida and Aspergillus spp. along with emerging echinocandin resistance in C. glabrata and C. auris raises the specter of untreatable multidrug resistant fungal infections, even as advances in medicine (cancer chemotherapy, organ transplant, premature infants, HIV/AIDS therapy) have increased the size of the vulnerable population. Our proposal aims to develop a novel broad spectrum antifungal therapeutic targeting Glycosylphosphatidylinositol (GPI) biosynthesis to treat life threatening infections due to drug resistant Candida and Aspergillus with no cross resistance to existing agents. Our Aims are: Aim 1 (Phase 1). Demonstrate improved efficacy is achievable by optimizing pharmacokinetic (PK) properties of the series. Perform metabolic identification (MetID) studies on M743, M720, and the hydrolyzed core lacking the sidechain to identify oxidative metabolic hotspots to guide a limited Lead Optimization (Lead Opt) effort to improve PK properties of the series while maintaining potency, spectrum, target selectivity, and minimizing cytotoxicity. Test up to 2 new analogs in a murine systemic infection model of Candidiasis with and without 1-aminobenzotriazole (ABT) PK enhancer codosing. Milestone 1. Based on MetID studies, synthesize up to 30 new M743 analogs. An analog showing an IP-administered dose-dependent > 3 log10 reduction in fungal burden in a murine Candidiasis model (i.e. superior to M720 efficacy) with or without ABT codosing will identify the key (and addressable) liability of the series and warrant advancement of the program to Ph 2. Aim 2 (Phase 2). M743 scale up, Lead Opt and in vitro characterization of compounds. Produce M743 on scale sufficient to supply a full Lead Opt effort based on MetID data and emerging SAR. Characterize analogs as in Aim 1 with additional emphasis on PK, MOA, reduced serum binding, and cytotoxicity. Milestone 2. Obtain 3g of M743; semisynthesize up to 100 new analogs. Identify up to 3 analogs with acceptable potency and PK (without ABT codosing), along with validated target engagement, FOR <1 x 109, in vitro synergy with Gwt1 inhibitor, APX001A (FICI<0.5), progressible activity in serum, and acceptable toxicity (in vivo cytotoxicity vs. HepG2, in vitro IC50>10 uM vs ion channels, CYPs, critical PANLABS targets) to advance to Aim 3. Aim 3 (Phase 2). In vivo Characterization. Efficacy of up to 2 compounds will be tested in a murine Candidiasis (including codosing with APX001 to evaluate in vivo synergy) and Invasive Pulmonary Aspergillosis infection models without ABT codosing. Milestone 3. Semisynthesize 200 mg of each test compound. Demonstrate acceptable MIC90 across Candida/Aspergillus spp. Identify suitable formulation for IP dosing. Conduct dose-ranging studies to gauge exposures and tolerability at higher doses to guide dose selection. Top analog achieving dose-dependent efficacy in each infection model (> 3 log reduction in burden over therapeutic duration) and overall favorable drug-like properties will be selected as a preclinical candidate.

念珠菌和曲霉属中广泛存在唑类耐药性。以及新兴的棘白菌素 光滑念珠菌和耳念珠菌的耐药性引发了无法治疗的多重耐药真菌感染的担忧， 即使医学不断进步（癌症化疗、器官移植、早产儿、艾滋病毒/艾滋病治疗） 增加了弱势群体的规模。我们的建议旨在开发一种新颖的广谱 针对糖基磷脂酰肌醇 (GPI) 生物合成的抗真菌治疗可治疗危及生命的疾病 耐药念珠菌和曲霉菌引起的感染，与现有药物没有交叉耐药性。我们的 目标是： 目标 1（第一阶段）。证明通过优化药代动力学 (PK) 可以提高疗效 该系列的属性。对 M743、M720 和水解产物进行代谢鉴定 (MetID) 研究 缺乏侧链的核心无法识别氧化代谢热点，从而指导有限的先导优化（Lead Opt) 努力改善该系列的 PK 特性，同时保持效力、谱图、目标选择性和 最大限度地减少细胞毒性。在鼠念珠菌病全身感染模型中测试多达 2 种新的类似物 无需 1-氨基苯并三唑 (ABT) PK 增强剂共同给药。里程碑 1. 基于 MetID 研究，综合 多达 30 个新的 M743 类似物。类似物显示 IP 给药剂量依赖性 > 3 log10 减少 鼠念珠菌病模型中的真菌负荷（即优于 M720 功效），无论是否联合给药 ABT 确定该系列的关键（和可解决的）责任，并保证该计划推进到第二阶段。 目标 2（第 2 阶段）。 M743 放大、Lead Opt 和化合物的体外表征。生产M743 规模足以提供基于 MetID 数据和新兴 SAR 的全面先导选择工作。表征 与目标 1 中的类似物，额外强调 PK、MOA、降低的血清结合和细胞毒性。里程碑 2、获得M743 3g；半合成多达 100 种新类似物。鉴定最多 3 个具有可接受效力的类似物 和 PK（无 ABT 联合给药），以及经过验证的靶点参与，FOR <1 x 109，体外协同作用 Gwt1抑制剂，APX001A（FICI<0.5），血清中的渐进活性，以及​​可接受的毒性（体内细胞毒性） 与 HepG2 相比，体外 IC50>10 uM（与离子通道、CYP、关键 PANLABS 目标相比），以推进目标 3。 目标 3（第 2 阶段）。体内表征。最多 2 种化合物的功效将在小鼠身上进行测试 念珠菌病（包括与 APX001 共同给药以评估体内协同作用）和侵袭性肺部疾病 无需 ABT 联合给药的曲霉菌感染模型。里程碑 3. 每个测试半合成 200 mg 化合物。在念珠菌/曲霉属中表现出可接受的 MIC90。确定合适的 IP 配方 剂量。进行剂量范围研究，以评估较高剂量下的暴露和耐受性，以指导剂量 选择。顶级类似物在每种感染模型中实现剂量依赖性功效（负担减少> 3 log 超过治疗持续时间）和总体有利的药物样特性将被选择作为临床前候选药物。