Development of non-toxic amphotericin B derivatives targeting invasive fungal infections

开发针对侵袭性真菌感染的无毒两性霉素 B 衍生物

• 批准号: 10183149
• 负责人: David R Andes
• 金额: $ 71.44万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183149
• 关键词: Acute; Amphotericin B; Animal Model; Animals; Antifungal Agents; Aspergillosis; Bacterial Infections; Binding; Biophysics; Candidiasis; Canis familiaris; Cause of Death; Cells; Chemicals; Cholesterol; Chronic; Clinic; Clinical; Clinical Management; Complex; Critical Illness; Development; Dose; Dose-Limiting; Drug Interactions; Drug Kinetics; Drug Monitoring; Epithelial Cells; Ergosterol; Exhibits; FDA approved; Family; Formulation; Fungal Drug Resistance; Goals; Head; Human; Hybrids; Immunocompromised Host; In Vitro; Industrial fungicide; Infection; Life; Liposomes; Membrane; Modification; Molds; Molecular; Monitor; Mus; Mycoses; Natural Products; Nature; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacodynamics; Polyenes; Porifera; Positioning Attribute; Predisposition; Preparation; Rattus; Reporting; Research; Resistance; Resistance development; Safety; Series; Sterols; Structural Models; Synthesis Chemistry; Testing; The science of Mycology; Therapeutic; Therapeutic Index; Thinking; Time; Toxic effect; Treatment Protocols; Urea; Yeasts; base; biophysical properties; cell killing; chemical synthesis; clinical efficacy; clinically relevant; design; efficacy study; frontier; improved; in vivo; insight; medical specialties; mouse model; multidisciplinary; pathogen; pathogenic fungus; programs; renal epithelium; screening; side effect; trait; treatment strategy

1. Project Summary / Abstract Invasive fungal infections (IFI) are a leading cause of death in the growing number of immunocompromised patients, and successful therapy is notoriously difficult. Leading FDA-approved antifungal classes are limited by inadequate clinical efficacy, which is often due to dose-limiting toxicities, emerging resistance, drug-drug interactions, and the need for therapeutic monitoring. New antifungals with robust activity against a broad spectrum of pathogens, minimal susceptibility to resistance, and limited side effects are needed. Amphotericin B (AmB) demonstrates dose-dependent killing, is fungicidal, has exceptionally broad spectrum, and has no reported development of resistance. However, the commercially available forms of AmB, including AmBisome®, have both acute and chronic toxicities that preclude safe use at high doses. This toxicity hinders realization of the full clinical potential of AmB. Our goal is to develop a chemically modified AmB derivative with a broad spectrum of robust fungicidal activity, lack of resistance, and, most importantly, limited toxicity. This will enable clinicians to safely employ high-dose treatment protocols to more effectively treat IFI. Overturning half a century of prior thinking, we found that AmB primarily kills both fungal and human cells by simply binding ergosterol and cholesterol, respectively. Guided by this insight, we recently designed a new AmB derivative, C2’epiAmB, which selectively binds ergosterol over cholesterol. Accordingly, C2’epiAmB retains good fungicidal activity against many pathogens, and is non-toxic to human primary renal epithelial cells (hRECs), mice, and rats at the highest doses tested. However, C2’epiAmB also has important limitations with respect to potency and pathogen scope. Earlier studies from our labs identified AmB derivatives bearing urea motifs at C16 which show increased antifungal potency but retain unacceptable toxicities. In this research program, we will combine the toxicity-eliminating C2’ modification in C2’epiAmB with efficacy-promoting urea modifications at C16 to develop a new class of hybrid polyene fungicidal agents that are both non-toxic and highly effective in eradicating IFI. A representative hybrid derivative that we recently synthesized, C2'epiAmBAU, has excellent potency against a series of important pathogens and minimal toxicity in hRECs. Building on these and many other encouraging preliminary results, we now plan to synthesize a family of C2’epiAmBUreas and extensively characterize them in state-of-the-art biophysical, mechanistic, resistance, efficacy, and toxicity studies, to identify the most promising candidates for enabling a new ‘high-dose’ clinical paradigm for better treating IFI. To accomplish all these goals, we have assembled a world-class multidisciplinary team of experts in chemical synthesis, antifungal development, pharmacokinetics, molecular mycology, and the clinical management of IFI. At the end of this proposal, we will be positioned for IND-enabling studies with a potentially transformative new antifungal agent.

1.项目总结/摘要 侵袭性真菌感染（IFI）是越来越多的人死亡的主要原因， 免疫功能低下的患者，成功的治疗是众所周知的困难。领先的FDA批准 抗真菌剂的种类受到临床疗效不足的限制，这通常是由于剂量限制性毒性， 新出现的耐药性、药物间相互作用以及治疗监测的需要。新的抗真菌药物， 对广谱病原体具有强大的活性，对耐药性的敏感性极小，且副作用有限 需要效果。两性霉素B（AmB）显示出剂量依赖性杀伤作用，是杀真菌的，具有 特别是广谱的，并且没有报道耐药性的发展。然而，商业上 AmB的可用形式，包括AmBisome®，具有急性和慢性毒性， 高剂量这种毒性阻碍了AmB的全部临床潜力的实现。我们的目标是发展一个 化学修饰的AmB衍生物具有广谱的强杀真菌活性，缺乏抗性， 最重要的是，毒性有限。这将使临床医生能够安全地采用高剂量治疗方案， 更有效地治疗IFI。我们推翻了半个世纪以来的传统观点，发现AmB主要杀死 真菌和人类细胞通过简单地结合麦角固醇和胆固醇。在这种认识的指导下，我们 最近设计了一种新的AmB衍生物C2'epiAmB，它选择性地结合麦角固醇而不是胆固醇。 因此，C2'epiAmB保留了对许多病原体的良好杀真菌活性，并且对人类无毒 原代肾上皮细胞（hREC），小鼠和大鼠在最高剂量测试。然而，C2'epiAmB也 在效力和病原体范围方面具有重要的局限性。我们实验室的早期研究发现 在C16处带有脲基序的AmB衍生物显示出增加的抗真菌效力，但保留了不可接受的抗真菌活性。 毒性在这项研究计划中，我们将联合收割机将C2'epiAmB中的毒性消除C2'修饰与 在C16处进行促进功效的脲修饰，以开发一类新的杂合多烯杀真菌剂， 都是无毒的，而且对根除IFI非常有效。一种代表性的混合衍生产品，我们最近 合成的C2'epiAmBAU对一系列重要病原体具有优异的效力， hREC中的毒性。在这些和许多其他令人鼓舞的初步成果的基础上，我们现在计划 合成C2 ′ epiAmBureas家族并在最先进生物物理学， 机制，抗性，功效和毒性研究，以确定最有前途的候选人，使一个 新的“高剂量”临床范例，以更好地治疗IFI。为了实现所有这些目标，我们组织了一个 世界一流的多学科专家团队，在化学合成，抗真菌开发，药代动力学， 分子真菌学和IFI的临床管理。在本提案结束时，我们将定位为 一种具有潜在变革性的新型抗真菌剂的IND使能研究。