Developing a New Therapeutic for the Treatment of Invasive Aspergillosis

开发治疗侵袭性曲霉菌病的新疗法

• 批准号: 8522961
• 负责人: MITCHELL W MUTZ
• 金额: $ 30万
• 依托单位: AMPLYX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-18 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522961
• 关键词: Accounting; Acute; Affinity; Americas; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Binding; Bone Marrow Transplantation; Calcineurin; Calcineurin Pathway; Calcineurin inhibitor; Candidiasis; Caspofungin; Cause of Death; Cell Wall; Cell physiology; Chemicals; Chemistry; Clinical; Communicable Diseases; Computer Simulation; Cyclosporine; Cytochrome P450; Data; Development; Disease; Drug Kinetics; Drug resistance; Eukaryota; FDA approved; FK506; Fungal Drug Resistance; Genetic; Goals; Growth; Health Care Costs; Homology Modeling; Human; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Industrial fungicide; Infection; Investigation; Knowledge; Libraries; Michigan; Molds; Mycoses; Organ; Outcome; Parents; Pathogenesis; Patients; Permeability; Physiology; Process; Proteins; Publishing; Relative (related person); Resistance; Roentgen Rays; Saccharomyces cerevisiae; Sales; Sequence Homology; Societies; Solid; Specificity; Structure; Structure-Activity Relationship; Tacrolimus Binding Protein 1A; Testing; Therapeutic; Therapeutic Index; Toxic effect; Translating; Transplant Recipients; Treatment outcome; United States; Universities; Virulence; Voriconazole; Work; analog; base; biological adaptation to stress; calcineurin phosphatase; clinical efficacy; clinically relevant; cost; data modeling; design; economic cost; effective therapy; fungus; improved; in vitro activity; innovation; insight; model design; mortality; next generation; novel; novel therapeutics; pathogen; patient population; preclinical study; prevent; professor; public health relevance; resistant strain; response; screening; small molecule

DESCRIPTION (provided by applicant): Invasive aspergillosis (IA), caused by the fungus Aspergillus fumigatus, is associated with mortality rates of 40- 50%. In response to the lack of effective treatments, the Infectious Diseases Society of America highlighted A. fumigatus as one of only six pathogens for which it mandated that a "substantive breakthrough is urgently needed". IA accounts for the largest financial burden of all invasive fungal infections, with an annual economic cost in the United States of over $1.1 billion. Driven by the growing immunosuppressed patient population, both the incidence and mortality due to A. fumigatus have risen three-fold in the last decade. While much is known regarding the cellular processes required for fungal pathogenesis, translating understanding into tangible clinical benefit has been difficult due to the fact that these fungal pathogens and their hosts have similar physiology. As a result, current antifungal agents have limited clinical efficacy, are poorly fungicidal in the host, are occasionally toxic, and are increasingly ineffective due to emerging resistance. Thus, innovative antifungal targeting agents and strategies are critically needed. It has been well established that molecules targeting fungal calcineurin (FC) have extremely potent antifungal activity against a broad range of fungi. Over the past decade, our collaborator has established that calcineurin is required for A. fumigatus hyphal growth and virulence. Moreover, calcineurin is required for fungal stress response and small molecule or genetic inhibition of calcineurin thwarts drug resistance. The challenge of exploiting FC as an antifungal agent is due to structural and sequence homology with human calcineurin (HC). Knowledge of the HC pathway and the immunosuppressive capacity of calcineurin inhibition has been one of the greatest contributions to our current solid organ and bone marrow transplantation abilities. However, inhibition of HC causes severe immunosuppression and toxicity. Recent chemical innovations have enabled Amplyx to rapidly create libraries of analogues of FK506 and FK520 that were previously synthetically intractable. These new chemistries have resulted in promising analogs with substantially lower immunosuppression than the parent compounds yet maintain a high-degree of antifungal activity. Based on these preliminary results, our goals in this proposal are to (1) Use existing structural data and perform computational modeling to design non-immunosuppressive calcineurin inhibitors of A. fumigatus; (2) Synthesize and purify a library of these calcineurin inhibitors for initial testing; and (3) Screen and select these compounds for low immunosuppression, potent antifungal activity, and favorable pharmacokinetics. The impact of this work will be to utilize a structural biologic approach to design, synthesize, and test fungal-specific calcineurin inhibitors with minimal immunosuppressive action and robust antifungal activity against both A. fumigatus wild-type and antifungal resistant strains, potentially transforming the treatment paradigm for IA.

描述（由申请人提供）：由真菌烟曲霉引起的侵袭性曲霉菌病 (IA) 与 40-50% 的死亡率相关。由于缺乏有效的治疗方法，美国传染病学会强调烟曲霉是其“迫切需要取得实质性突破”的六种病原体之一。 IA 是所有侵袭性真菌感染中最大的经济负担，在美国每年造成的经济损失超过 11 亿美元。在免疫抑制患者人数不断增长的推动下，烟曲霉的发病率和死亡率在过去十年中增加了三倍。尽管人们对真菌发病机制所需的细胞过程了解很多，但由于这些真菌病原体及其宿主具有相似的生理学，因此将理解转化为切实的临床益处一直很困难。因此，目前的抗真菌药物临床疗效有限，对宿主的杀真菌作用很差，偶尔有毒，并且由于出现耐药性而越来越无效。因此，迫切需要创新的抗真菌靶向药物和策略。众所周知，针对真菌钙调神经磷酸酶 (FC) 的分子对多种真菌具有极强的抗真菌活性。在过去的十年中，我们的合作者已经确定钙调磷酸酶是烟曲霉菌丝生长和毒力所必需的。此外，钙调磷酸酶是真菌应激反应所必需的，并且钙调磷酸酶的小分子或基因抑制可阻止耐药性。利用 FC 作为抗真菌剂的挑战是由于其与人钙调神经磷酸酶 (HC) 的结构和序列同源性。对 HC 途径和钙调神经磷酸酶抑制的免疫抑制能力的了解是对我们当前实体器官和骨髓移植能力的最大贡献之一。然而，抑制 HC 会导致严重的免疫抑制和毒性。最近的化学创新使 Amplyx 能够快速创建 FK506 和 FK520 类似物库，而这些以前在合成上很难处理。这些新的化学物质产生了有前途的类似物，其免疫抑制显着低于母体化合物，但仍保持高度的抗真菌活性。基于这些初步结果，我们在本提案中的目标是（1）使用现有的结构数据并进行计算建模来设计烟曲霉的非免疫抑制性钙调神经磷酸酶抑制剂； (2) 合成并纯化这些钙调神经磷酸酶抑制剂库以进行初步测试； (3) 筛选并选择这些化合物的低 免疫抑制、有效的抗真菌活性和良好的药代动力学。这项工作的影响将是利用结构生物学方法来设计、合成和测试真菌特异性钙调神经磷酸酶抑制剂，这些抑制剂对烟曲霉野生型和抗真菌耐药菌株具有最小的免疫抑制作用和强大的抗真菌活性，有可能改变 IA 的治疗模式。