Target identification and structure optimization of novel thiazole antifungals

描述（由申请人提供）：目前全身性真菌感染的治疗选择仍然有限。由于真菌和宿主细胞在结构和代谢方面的相似性，以及由此产生的潜在宿主毒性，新的抗真菌药物的开发变得复杂。常用的以真菌细胞膜固醇为靶点的多烯和三唑类抗真菌药物也会影响哺乳动物细胞膜胆固醇的稳定性和生成。最近开发的棘白菌素对真菌靶点更有特异性，但对荚膜组织浆体和新型隐球菌治疗无效，使宿主毒性多烯和三唑成为治疗这些病原体引起的感染的唯一方法。从与嘌呤结构相似的小分子（如ATP/GTP， NADP等）的文库中，我们发现了一系列以噻唑为基础的化合物，它们对荚膜组织浆体和新型隐球菌具有有效的抗真菌活性。重要的是，这些化合物不仅抑制培养的真菌细胞，而且抑制感染后驻留在哺乳动物宿主细胞内的真菌细胞。噻唑类抗真菌药物治疗组织浆感染的巨噬细胞可保护宿主细胞免受组织浆诱导的细胞死亡。为了使最热门的抗真菌噻唑成为药物开发的主要候选药物，并更好地了解其作用模式，本研究计划寻求利用亲和力和化学蛋白质组学来确定抗真菌噻唑的细胞靶点，并利用动物模型提供初步的体内疗效和毒性研究。此外，将制备并测试噻唑衍生物，以确定抗真菌活性和抗真菌活性所需的结构特征

DESCRIPTION (provided by applicant): Current treatment options for systemic fungal infections remain limited. The development of new antifungals is complicated by the structural and metabolic similarities among fungal and host cells, and the consequent potential for host toxicity. The commonly used polyene and triazole antifungals, which target fungal cell membrane sterols, also affect the stability and production of mammalian cell membrane cholesterol. The recently developed echinocandins are more specific for fungal targets, however they are ineffective in the treatment of Histoplasma capsulatum and Cryptococcus neoformans, leaving the host-toxic polyenes and triazoles as the only methods for treatment of infections caused by these pathogens. From a library of small molecules with structural similarities to purines (e.g., ATP/GTP, NADP, etc.), we identified a series of thiazole-based compounds that have potent antifungal activity against Histoplasma capsulatum and Cryptococcus neoformans. Importantly, these compounds inhibit not only fungal cells in culture but also fungal cells that reside within mammalian host cells following infection. Treatment of Histoplasma-infected macrophages with the thiazole-based antifungals protects host cells from Histoplasma- induced cell death. To mature the top hit antifungal thiazole into a lead candidate for drug development and to better understand its mode of action, this research proposal seeks to identify the cellular target(s) of the antifungal thiazole using affinity and chemical proteomics and to provide initial n vivo efficacy and toxicity studies using an animal model. In addition, derivatives of the thiazole will be prepared and tested to define the structural features necessary for antifungal activity and to improve its chemical properties and maximize antifungal potency.