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

抗真菌药：β(1,6)-葡聚糖合成抑制剂

• 批准号: 6643954
• 负责人: Claude P Selitrennikoff
• 金额: $ 10万
• 依托单位: MYCOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643954
• 关键词: Candida albicans; antifungal agents; candidiasis; carbohydrate biosynthesis; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; glucans; inhibitor /antagonist; laboratory mouse

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.

描述（由申请人提供）：真菌引起广泛的疾病状态。最常见的例子是相对轻微的局部皮肤和粘膜感染，如脚癣、阴道酵母菌感染和角化指甲感染。然而，越来越多的真菌引起全身疾病，并累及内脏器官。这些已经成为严重和危及生命的问题，很难诊断，对宿主防御机制受损的患者来说，治疗更具挑战性。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复合物的多烯（例如两性霉素B），抑制麦角甾醇生物合成途径步骤的一些唑和烯丙胺，抑制核酸合成的氟胞嘧啶，以及Cancidas(r)，一种β(1,3)-葡聚糖合成酶抑制剂。不幸的是，两性霉素B有许多急性和慢性副作用。氟胞嘧啶具有狭窄的活性谱，并且由于耐药真菌的发展而受到治疗失败的困扰。唑类药物仅具有抑菌作用，对常用唑类药物的耐药性已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型抗真菌药物。我们的长期目标是发现一种新的抗真菌药物，它在合成一种必需的细胞壁聚合物，即β(1,6)葡聚糖中具有活性。人类缺乏的β(1,6)葡聚糖的合成对真菌生长至关重要，并且代表了抗真菌药物开发的未开发途径。我们将通过三个具体目标来实现这一目标：一：使用已建立和验证的体外试验筛选5000种β(1,6)-葡聚糖合成抑制剂化合物。第二：测试Aim 1中鉴定的化合物对许多人类真菌病原体的活性，并确认每种化合物抑制β(1,6)-葡聚糖的合成。三：测试化合物对哺乳动物细胞的毒性和对白色念珠菌感染的体内模型的有效性。最终，这项工作将导致分离出用于治疗人类真菌疾病的新型化合物。我们预测，由于人类没有β(1,6)葡聚糖合成的途径，抑制剂将是安全有效的治疗方法。