Therapeutic Agents Targeting Cryptococcal Infections

隐球菌属是临床上一组重要的可导致生命的机会性真菌病原体 威胁疾病，特别是在免疫功能低下的患者群体中。从历史上看，这涉及到 晚期艾滋病毒携带者，但在其他可免疫排卵人群中正变得更加普遍。初级阶段 病原体，新生葡萄球菌和加蒂埃葡萄球菌，在环境中无处不在，这为 吸入相应的孢子或酵母菌即可确诊为原发肺部感染。不幸的是，许多人 肺部隐球菌病的病例可进展并导致致命的播散性真菌感染。特别之处 重要的是病原体强烈偏好(~90%)在中枢神经系统内建立感染 系统，尤其是通过感染脑膜导致隐球菌性脑膜炎。这是主要原因 全世界脑膜炎的发病率很高，死亡率很高(约80%)。隐球菌病的治疗 由于可供选择的有效治疗方法数量有限，因此感染是困难的。许多人的困难 有效穿越血脑屏障并达到治疗相关浓度的抗真菌药物 在CNS内，目前的治疗选择仅限于三种药物：氟康唑、5-氟胞嘧啶和两性霉素。 新城疫流行株对氟康唑和5-氟胞嘧啶耐药水平的演变 隐球菌已经显著地破坏了这些药物，而与两性霉素相关的毒性是 众所周知的问题。基于治疗这些危及生命的感染的有限选择，有一种 迫切需要开发能够到达中枢神经系统的更有效的药物。QMD正在开发抗真菌药物 抑制基本酶二氢叶酸还原酶(DHFR)的抗叶酸。虽然DHFR在临床上是一种 在恶性疟原虫和弓形虫等几种真核病原体中的验证靶点， 利用这一目标进行抗真菌药物开发的努力远远落后。QMD发现了一种新的 具有高水平抗真菌活性和初始剂量耐受性的隐球菌类抑制剂 药代动力学研究表明，该化合物具有良好的体内疗效。 感染的动物模型。在这一阶段的应用中，我们将努力推进这一计划的治疗 隐球菌感染的研究(1)抗菌谱、PK/PD研究及机制探讨(S) 抗性，(2)探索结构修饰以提高对宿主酶的选择性指数，以及(3) 在小鼠感染模型中评价先导化合物和后备化合物。在证明中成功演示 体内效应的概念将使我们能够进一步推动这些抗真菌候选药物走向临床应用。

Cryptococcus species are a clinically important group of opportunistic fungal pathogens that can cause life threatening disease, particularly in the immunocompromised patient population. Historically, this has involved patients with advanced HIV, but is becoming more prevalent in other immunovulnerable populations. The primary pathogens, C. neoformans and C. gattii, are ubiquitous in the environment which provides ample opportunity to establish primary pulmonary infections upon inhalation of the corresponding spore or yeast. Unfortunately, many cases of pulmonary cryptococcosis can progress and lead to deadly disseminated fungal infections. Of special importance is the strong preference (~90%) for the pathogen to establish infection within the central nervous system, especially through infection of the meninges leading to cryptococcal meningitis. This is the leading cause of meningitis world-wide and is associated with a very high mortality rate (~80%). Treatment of cryptococcal infections is difficult owing to the limited number of effective treatment options available. The difficulty of many antifungal drugs to effectively traverse the blood-brain barrier and reach therapeutically relevant concentration within the CNS limits current treatment options to just three agents: fluconazole, 5-flucytosine and amphotericin. The evolution of substantial levels of resistance to fluconazole and 5-flucytosine in circulating strains of Cryptococcus has significantly undermined these agents while the toxicities associates with amphotericin are a well-known problem. Based on the limited options for treating these life-threatening infections, there is a compelling need to develop more effective agents capable of reaching the CNS. QMD is developing antifungal antifolates that inhibit the essential enzyme dihydrofolate reductase (DHFR). Although DHFR is a clinically validated target in several eukaryotic pathogens such as Plasmodium falciparum and Toxoplasma gondii, the efforts to exploit this target for antifungal drug development has lagged far behind. QMD has identified a novel inhibitor against Cryptococcus that is characterized by high levels of antifungal activity while initial dose-tolerance and pharmacokinetic studies suggest the compound has a favorable profile to demonstrate in vivo efficacy in animal models of infection. In this Phase I application, we will work to advance this program for the treatment of cryptococcal infections by (1) antimicrobial profiling, PK/PD studies and elucidation of mechanism(s) of resistance, (2) exploring structural modifications to increase the selectivity index over the host enzyme, and (3) evaluation of lead and back-up compounds in murine models of infection. Successful demonstration in proof-of- concept in vivo efficacy will enable us to further advance these antifungal candidates toward clinical application.