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; 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.

念珠菌和曲霉属之间的广泛抗烷基耐药性。以及新兴的echinocandin C. glabrata和C. ouris中的抗性提高了不可治疗的多药耐药真菌感染的幽灵， 即使医学进展（癌症化疗，器官移植，早产婴儿，艾滋病毒/艾滋病治疗） 增加了脆弱人群的规模。我们的建议旨在开发一种新颖的广泛范围 抗真菌治疗性靶向糖基磷脂酰肌醇（GPI）生物合成以治疗威胁生命 由于耐药性念珠菌和曲霉而引起的感染，对现有药物没有跨阻力。我们的 目的是： 目标1（阶段1）。通过优化药代动力学（PK），可以证明提高功效可以提高功效 该系列的属性。对M743，M720进行代谢识别（METID）研究 缺乏侧链的核心无法识别氧化代谢热点以指导有限的铅优化（铅 选择）努力提高该系列的PK性能，同时保持效力，频谱，目标选择性和 最小化细胞毒性。用和和 没有1-氨基苯甲酸（ABT）PK增强子编码。里程碑1。基于Metid研究，合成 最多30个新的M743类似物。一个模拟显示IP剂量依赖性> 3 log10降低的模拟 带有或没有ABT编码的鼠类念珠菌病模型中的真菌负担（即优于M720功效） 确定该系列的密钥（和可寻址）责任，并确定该计划将其提升到ph 2。 AIM 2（阶段2）。 M743缩放，铅OPT和化合物的体外表征。产生M743 规模足以根据METID数据和新兴SAR提供完整的潜在客户OPT努力。特征 类似物如AIM 1中，对PK，MOA，血清结合减少和细胞毒性的额外重视。里程碑 2。获得M743的3G；半合成最多100个新类似物。识别多达3个具有可接受效力的类似物 和PK（无需ABT编码），以及经过验证的目标参与，<1 x 109，体外协同作用 GWT1抑制剂，APX001A（FICI <0.5），血清中的进度活性和可接受的毒性（体内细胞毒性 vs. HEPG2，体外IC50> 10 UM与离子通道，CYP，临界Panlabs目标）以前进到AIM 3。 目标3（阶段2）。体内表征。多达2种化合物的功效将在鼠中测试 念珠菌病（包括与APX001编码以评估体内协同作用）和侵入性肺 曲霉病感染模型没有ABT编码。里程碑3。半特定每个测试的200毫克 化合物。在念珠菌/曲霉属中展示可接受的MIC90。确定适合IP的配方 给药。进行剂量范围的研究以衡量较高剂量的暴露和耐受性以指导剂量 选择。在每个感染模型中达到剂量依赖性效力的顶部模拟（> 3日志减轻负担 在治疗持续时间内）和总体有利的药物样特性将被选为临床前候选者。