Developing a New Therapeutic for the Treatment of Invasive Aspergillosis

描述（由申请人提供）：由烟曲霉引起的侵袭性曲霉病（IA）与40- 50%的死亡率有关。由于缺乏有效的治疗方法，美国传染病学会（Infectious Diseases Society of America）强调，烟曲霉是“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。由于免疫抑制患者人数的增加，烟曲霉的发病率和死亡率在过去十年中上升了三倍。虽然对真菌发病机制所需的细胞过程有很多了解，但由于这些真菌病原体及其宿主具有相似的生理机能，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较差，偶尔有毒性，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。研究表明，以真菌钙调磷酸酶（FC）为靶点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，我们的合作者已经确定了钙调磷酸酶是烟曲霉菌丝生长和毒力所必需的。此外，真菌的应激反应需要钙调磷酸酶，小分子或遗传抑制钙调磷酸酶可以阻止耐药性。利用FC作为抗真菌药物的挑战是由于其结构和序列与人钙调磷酸酶（HC）同源。了解HC途径和钙调磷酸酶抑制的免疫抑制能力是我们目前实体器官和骨髓移植能力的最大贡献之一。然而，抑制HC会引起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类似物的文库。这些新的化学物质已经产生了有希望的类似物，其免疫抑制比母体化合物低得多，但仍保持高度的抗真菌活性。基于这些初步结果，我们的目标是：(1)利用现有的结构数据并进行计算建模来设计烟曲霉非免疫抑制性钙调磷酸酶抑制剂；(2)合成并纯化这些钙调磷酸酶抑制剂文库，用于初步测试；(3)筛选这些化合物用于低剂量

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.