Antifungal drugs: Beta(1,6)-glucan synthesis inhibitors

描述(申请人提供)：真菌导致多种疾病状态。最常见的例子是相对轻微的局部皮肤和粘膜感染，如脚气、阴道酵母菌感染和角化指甲感染。然而，不祥的是，真菌数量的增加会导致内脏受累的全身性疾病。这些已经成为严重的、危及生命的问题，对于宿主防御机制受损的患者来说，这些问题很难诊断，甚至更难治疗。治疗真菌感染的部分困难，特别是在免疫功能低下的宿主中，是有限的抗真菌药物。目前可用的药物包括与真菌膜麦角甾醇形成络合物的多烯(例如两性霉素B)、抑制麦角甾醇生物合成途径步骤的一些氮唑和烯丙胺、抑制核酸合成的氟胞嘧啶以及β(1，3)-葡聚糖合成酶抑制剂Canidas(R)。不幸的是，两性霉素B有许多急性和慢性不良反应。氟胞嘧啶的活性范围很窄，由于耐药真菌的发展，治疗失败的情况时有发生。唑类药物只具有抗真菌作用，对常用的唑类药物的耐药性正成为一个重要的临床问题。人们普遍认为，迫切需要具有不同于现有药物作用机制的新的抗真菌药物。我们的长期目标是发现在合成一种重要的细胞壁聚合物，即β(1，6)葡聚糖中具有活性的新型抗真菌药物。β(1，6)葡聚糖的合成是真菌生长所必需的，也是抗真菌药物开发的一条未被开发的途径。我们将通过三个具体目标来实现这一点：第一：使用已建立和验证的体外试验筛选5,000个化合物以寻找β(1，6)-葡聚糖合成抑制剂。第二：测试目标一中确定的化合物对一些人类真菌病原体的活性，并确认每个化合物都抑制β(1，6)-卢康的合成。三：在白色念珠菌感染的活体模型中，测试化合物对哺乳动物的细胞毒性和有效性。最终，这项工作将导致分离出治疗人类真菌疾病的新类化合物。我们预测，由于人类没有合成β(1，6)葡聚糖的途径，抑制剂将是安全有效的治疗药物。

DESCRIPTION (provided by applicant): Fungi cause a wide spectrum of disease states. The most common examples are relatively minor, localized infections of the skin and mucous membranes such as athlete's foot, vaginal yeast infections, and infections of keratinized nails. However, an ominously increasing number of fungi cause systemic disease with the involvement of internal organs. These have become serious and life-threatening problems that are very difficult to diagnose and even more challenging to treat in patients with impaired host-defense mechanisms. Part of the difficulty in treating fungal infections, especially in immunocompromised hosts, is the limited armamentarium of antifungal drugs. Currently-available drugs include polyenes (e.g., amphotericin B) that complex with fungal-membrane ergosterol, a number of azoles and allylamines that inhibit steps in the ergosterol biosynthetic pathway, flucytosine that inhibits nucleic acid synthesis, and Cancidas(r), a beta (1,3)- glucan synthase inhibitor. Unfortunately, amphotericin B has a number of acute and chronic adverse effects. Flucytosine has a narrow spectrum of activity and is plagued with treatment failures due to the development of resistant fungi. Azoles are only fungistatic and resistance to commonly used azoles is becoming a significant clinical problem. There is general agreement that there is a critical and immediate need for new antifungals with mechanisms of action different from current drugs. Our long-term goal is to discover novel antifungals that are active in the synthesis of an essential cell wall polymer, namely, beta (1,6) glucan. The synthesis of beta (1,6)glucan, which is absent in humans, is essential for fungal growth and represents an unexploited pathway for the development of antifungal drugs. We will accomplish this in three Specific Aims: One: Screen 5,000 compounds for beta (1,6)-glucan synthesis inhibitors using an established and validated in vitro assay. Two: Test compounds identified in Aim One for activity against a number of human fungal pathogens and to confirm that each compound inhibits beta (1,6)- lucan synthesis. Three: Test compounds for mammalian cell toxicity and for efficacy in an in vivo model of Candida albicans infection. Ultimately, this work will lead to the isolation of new classes of compounds for treatment of human fungal disease. We predict that, since humans do not have the pathway for beta (1,6) glucan synthesis, inhibitors will be safe and effective therapeutics.