A Computer Modeling Approach

描述：隐球菌性脑膜炎(CM)仍然是艾滋病毒阳性者死亡的一个重要原因，也是一个主要的世界性健康问题。在北美，感染艾滋病毒的急性CM患者感染后3个月内的死亡率估计为20%，尽管患者可以获得良好的卫生保健资源。仅在撒哈拉以南非洲，CM的影响就是毁灭性的：每年艾滋病毒阳性患者中估计有53万人死亡，而一般人口中每年死于结核病的人数为35万人。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的一线药物是两性霉素B(Amb)，一种杀菌剂静脉注射。给药剂，有时与氟胞嘧啶联合给药。AMB和替代脂质制剂静脉给药会引起副作用，包括肾毒性、白细胞减少和心律失常。虽然CM的高死亡率是多种因素造成的，但发现一种口服可用、有效的AMB替代品将为抗击这种毁灭性的疾病增加一个重要的治疗选择。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包括氟康唑和AMB在内的其他抗真菌药物联合使用。与Amb相比，钙调神经磷酸酶抑制剂(CI‘s)在体外对新生隐球菌显示出更好的效力。此外，将真菌CI与抗真菌三氮唑(如氟康唑或泊沙康唑)结合可产生杀菌组合，这可能会缩短维持治疗所需的时间，并有助于避免耐药隐球菌菌株的增加。这里提出的工作将是第一阶段项目的继续，在该项目中，我们能够展示使用一种新的真菌钙调神经磷酸酶抑制剂对耐药新生葡萄球菌的体内疗效。目的1.从第一阶段合成与6个早期先导化合物密切相关的类似物。目的2.体外表征化合物以促进进展。根据需要迭代库。目的3.研究化合物在体内的药代动力学和药效。

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.