Developing a New Therapeutic for the Treatment of Invasive Aspergillosis

描述(申请人提供)：侵袭性曲霉病(IA)，由真菌烟曲霉引起，死亡率为40%-50%。由于缺乏有效的治疗方法，美国传染病学会强调，烟曲霉菌是它要求“迫切需要取得实质性突破”的仅有的六种病原体之一。IA是所有侵袭性真菌感染中最大的经济负担，在美国每年的经济损失超过11亿美元。在不断增长的免疫抑制患者群体的推动下，烟曲霉菌的发病率和死亡率在过去十年中都上升了三倍。虽然关于真菌发病所需的细胞过程已知很多，但由于这些真菌病原体及其宿主具有相似的生理学，将理解转化为切实的临床益处一直是困难的。因此，目前的抗真菌药物临床疗效有限，在宿主中杀菌力差，偶尔有毒，并且由于新出现的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。在过去的十年里，我们的合作者已经证实，钙调神经磷酸酶是烟曲霉菌丝生长和毒力所必需的。此外，钙调神经磷酸酶是真菌应激反应所必需的，小分子或基因抑制钙调神经磷酸酶可抑制耐药性。开发Fc作为抗真菌药物的挑战是由于与人钙调神经磷酸酶(HC)的结构和序列同源性。了解HC途径和钙调神经磷酸酶抑制的免疫抑制能力是我们目前固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能够快速创建以前难以合成的FK506和FK520类似物的库。这些新的化学方法已经导致了有希望的类似物，免疫抑制显著低于母体化合物，但仍保持了高度的抗真菌活性。基于这些初步结果，我们在这个建议中的目标是(1)利用现有的结构数据和进行计算建模来设计烟曲霉菌的非免疫抑制钙调神经磷酸酶抑制剂；(2)合成和纯化这些钙调神经磷酸酶抑制剂的文库，用于初步测试；以及(3)筛选和选择这些化合物用于低密度脂蛋白 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设计、合成和测试真菌特异性钙调神经磷酸酶抑制剂，具有最小的免疫抑制作用和强大的抗真菌活性，对烟曲霉野生型和抗真菌耐药菌株，潜在地改变了IA的治疗模式。

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.