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。最常见的例子是皮肤和粘膜的局部感染相对较小，例如运动员的脚，阴道酵母菌感染以及角化指甲的感染。但是，数量不祥的真菌会导致全身性疾病与内部器官的参与。这些已经变得严重且威胁生命的问题很难诊断，甚至在宿主防御机制受损的患者中治疗更具挑战性。治疗真菌感染的一部分困难，尤其是在免疫功能低下的宿主中，是抗真菌药物的有限的武器库。当前可用的药物包括与真菌 - 膜甲虫麦内蛋白复合物的多烯元素（例如，两性霉素B），许多偶氮和烯丙基氨基抑制了麦角固醇生物合成途径中的步骤，抗甲状腺素，抗鞭毛蛋白，抑制核酸合成和cancidas和cancidas（r），beta（r），beta（1）。不幸的是，两性霉素B具有许多急性和慢性不良反应。鞭毛蛋白具有狭窄的活性范围，并且由于耐药性真菌的发展而受到治疗失败的困扰。 Azoles仅是局限性的，对常用唑的抗性的抗性正成为一个重大的临床问题。人们普遍认为，具有与当前药物不同的作用机制的新抗真菌群体有至关重要的需求。我们的长期目标是发现活性在合成必需细胞壁聚合物（即β（1,6）葡聚糖）中的新型抗真菌抗体。在人类中不存在的β（1,6）葡萄糖的合成对于真菌生长至关重要，代表了一种未开发的抗真菌药物的途径。我们将在三个特定的目标中完成此操作：一：屏幕β（1,6） - 葡聚糖合成抑制剂的筛选化合物，使用已建立和经过验证的体外测定法。第二个：AIM中鉴定出的测试化合物，用于对许多人类真菌病原体的活性，并确认每种化合物都抑制了β（1,6）-Lucan合成。三：哺乳动物细胞毒性的测试化合物和在白色念珠菌感染的体内模型中的功效。最终，这项工作将导致隔离新的化合物来治疗人类真菌疾病。我们预测，由于人类没有β（1,6）葡萄糖合成的途径，因此抑制剂将是安全有效的疗法。