A Computer Modeling Approach

产品说明：隐球菌性脑膜炎（CM）仍然是HIV阳性个体死亡的重要原因，也是全球主要的健康问题。在北美，尽管患者可以获得良好的医疗保健资源，但感染HIV的急性CM患者在感染后3个月内的估计死亡率为20%。仅在撒哈拉以南非洲，CM的影响是毁灭性的：估计每年有530，000例HIV阳性患者死亡，而普通人群中每年有350，000例结核病死亡。CM症状包括与颅内压升高相关的严重头痛、恶心和呕吐。目前治疗CM的一线治疗药物是两性霉素B（AmB），这是一种杀真菌的静脉内给药药物，有时与氟胞嘧啶联合给药。AmB和替代脂质制剂静脉内给药并引起副作用，包括肾毒性、白细胞减少症和心律失常。虽然多种因素导致CM的高死亡率，但发现口服有效的AmB替代品将为对抗这种毁灭性疾病增加重要的治疗选择。我们建议利用真菌钙调神经磷酸酶（一种重要的膜应激反应蛋白）来创造一类新的抗真菌药物。通过我们的合作者Joe Heitman和其他人的工作，已经表明靶向真菌钙调神经磷酸酶在治疗隐球菌疾病方面具有巨大的潜力，无论是作为单一疗法还是与其他抗真菌药物（包括氟康唑和AmB）联合使用。钙调神经磷酸酶抑制剂（CI's）在体外对新生隐球菌的作用比AmB强上级。此外，将真菌CI与真菌抑制性三唑如氟康唑或泊沙康唑组合产生杀真菌组合，这可能减少维持治疗所需的时间，并有助于避免耐药隐球菌菌株的发生率增加。这里提出的工作将是I期项目的继续，在该项目中，我们能够证明与耐药的C菌株相比的体内功效。使用新型真菌钙调磷酸酶抑制剂的新型真菌。目标1。生成来自第一阶段的6种早期先导化合物的密切相关的类似物。目标2.在体外表征化合物以促进发展。根据需要迭代库。目标3.在体内表征化合物的药代动力学和功效。

DESCRIPTION: Cryptococcal meningitis (CM) continues to be a significant cause of mortality among HIV positive individuals, and a major worldwide health concern. The estimated mortality rate for HIV-infected acute CM patients is 20% within 3 months after infection in North America, despite patient access to good health care resources. In sub- Saharan Africa alone, the effects of CM are devastating: an estimated 530,000 annual deaths among HIV positive patients compared with 350,000 annual deaths for tuberculosis in the general population. CM symptoms include severe headaches, nausea, and vomiting related to increased intracranial pressure. The first line therapeutic to treat CM is currently Amphotericin B (AmB), a fungicidal i.v. administere agent, and is sometimes co-administered with flucytosine. AmB and alternative lipid formulations are administered intravenously and cause side effects including nephrotoxicity, leukopenia, and cardiac arrhythmia. Although multiple factors contribute to the high mortality rates of CM, the discovery of an orally available, efficacious alternative to AmB would add an important treatment option to combat this devastating illness. We propose exploiting fungal calcineurin, an essential membrane stress response protein, to create a new class of antifungals. Through the work of our collaborator, Joe Heitman, and others, it has been shown that targeting fungal calcineurin has great potential in treating cryptococcal disease, both as monotherapy and in combination with other antifungals including fluconazole and AmB. Calcineurin inhibitors (CI's) exhibit superior in vitro potency compared with AmB against Cryptococcus neoformans. In addition, combining a fungal CI with a fungistatic triazole such as fluconazole or posaconazole results in a fungicidal combination which would likely reduce the time period required for maintenance therapy and help avoid the increased incidence of resistant cryptococcal strains. The work proposed here will be a continuation of a Phase I project where we were able to demonstrate in vivo efficacy vs. a drug resistant strain of C. neoformans employing a novel fungal calcineurin inhibitor. Aim 1. Generate closely related analogs of the 6 early lead compounds from Phase I. Aim 2. Characterize compounds in vitro for advancement. Iterate library as required. Aim 3. Characterize compounds in vivo for pharmacokinetics and efficacy.