Therapeutic Agents Targeting Cryptococcal Infections

针对隐球菌感染的治疗药物

• 批准号: 10697960
• 负责人: Dennis L. Wright
• 金额: $ 30万
• 依托单位: QUERCUS MOLECULAR DESIGN, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-08 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697960
• 关键词: Amphotericin; Amphotericin B; Animal Model; Annual Reports; Antifungal Agents; Area; Binding Proteins; Blood - brain barrier anatomy; Case Study; Central Nervous System; Cessation of life; Clinical; Columbidae; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; Development; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Disease; Dose; Drug Kinetics; Drug Targeting; Drug or chemical Tissue Distribution; Drug resistance; Elements; Encapsulated; Environment; Enzymes; Evaluation; Event; Evolution; Feces; Fluconazole; Fluconazole resistance; Flucytosine; Folic Acid Antagonists; Formulation; Goals; HIV; Health; Hematogenous Spread; Homelessness; Human; Immune system; Immunocompromised Host; In Vitro; Individual; Infection; Infiltration; Inhalation; Kinetics; Lead; Life; Lung; Lung infections; Measurable; Meninges; Meningitis; Metabolic; Metabolic Pathway; Metabolism; Modeling; Modification; Mus; Mycoses; Opportunistic Infections; Organ; Organism; Outcome; Pathogenicity; Patients; Phase; Plasmodium falciparum; Population; Property; Regimen; Reproduction spores; Resistance; Risk; Route; Series; Small Business Technology Transfer Research; Soil; Sulfamethoxazole; Therapeutic; Toxic effect; Toxoplasma gondii; Treatment Cost; United States; Work; Yeasts; advanced disease; analog; antimicrobial; blood-brain barrier crossing; brain tissue; clinical application; design; drug development; effective therapy; efficacy evaluation; efficacy study; experimental study; fungus; immunosuppressed; improved; in vivo; in vivo evaluation; indexing; inhibitor; lead candidate; lead optimization; medically underserved population; mortality; mouse model; novel; novel therapeutics; nucleic acid biosynthesis; pathogen; pathogenic fungus; patient population; pharmacokinetics and pharmacodynamics; preclinical evaluation; preference; resistance mechanism; scale up; synergism; targeted treatment; therapeutic candidate; treatment planning; treatment program

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.

隐球菌属是一组临床上重要的机会致病真菌，可导致生命 威胁性疾病，特别是在免疫功能低下的患者群体中。历史上，这涉及到 晚期HIV患者，但在其他免疫脆弱人群中越来越普遍。主 病原体、C.新型隐球菌和gattii，在环境中无处不在，这提供了充足的机会， 吸入相应的孢子或酵母菌后会导致原发性肺部感染。不幸的是很多 肺隐球菌病的病例可以进展并导致致命的播散性真菌感染。特殊 重要的是病原体在中枢神经系统内建立感染的强烈偏好（~90%） 隐球菌性脑膜炎是一种通过脑膜感染引起的脑膜炎。这是导致 脑膜炎是世界范围内最常见的脑膜炎，并且与非常高的死亡率（~80%）相关。隐球菌病的治疗 由于现有的有效治疗选择有限，感染很难控制。许多人的困难 抗真菌药物有效地穿过血脑屏障并达到治疗相关浓度 目前的治疗选择仅限于三种药物：氟康唑、5-氟胞嘧啶和阿替霉素。 大肠埃希菌对氟康唑和5-氟胞嘧啶耐药水平的演变 隐球菌已显着破坏这些药物，而毒性与阿替西霉素是一个 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， 迫切需要开发能够到达CNS的更有效的药剂。QMD正在开发抗真菌药物 抑制必需酶二氢叶酸还原酶（DHFR）的抗叶酸剂。虽然DHFR在临床上是一种 在几种真核病原体如恶性疟原虫和刚地弓形虫中， 利用该靶点进行抗真菌药物开发的努力远远落后。QMD发现了一种新的 隐球菌抑制剂，其特征在于高水平的抗真菌活性，同时初始剂量耐受 和药代动力学研究表明，该化合物具有有利的特性，以证明在体内对 感染的动物模型。在第一阶段的申请中，我们将努力推进这一计划， 隐球菌感染通过（1）抗菌谱、PK/PD研究和阐明 抗性，（2）探索结构修饰以增加对宿主酶的选择性指数，以及（3） 在鼠感染模型中评价先导化合物和备用化合物。在证明中的成功演示- 体内疗效的概念将使我们能够进一步推进这些抗真菌候选药物的临床应用。