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.

隐球菌属是临床上重要的一组机会性真菌病原体，可导致生命 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 晚期艾滋病毒患者，但在其他免疫脆弱人群中变得更加普遍。初级 病原体，新型隐球菌和格特隐球菌，在环境中普遍存在，这为它们提供了充分的机会 吸入相应的孢子或酵母后引起原发性肺部感染。不幸的是，许多 肺隐球菌病病例可能会进展并导致致命的播散性真菌感染。特殊的 重要性在于病原体强烈偏好（~90%）在中枢神经内建立感染 系统，特别是通过脑膜感染导致隐球菌性脑膜炎。这是主要原因 脑膜炎是世界范围内流行的疾病，死亡率非常高（~80%）。隐球菌的治疗 由于可用的有效治疗方案数量有限，感染很难发生。很多人的困难 抗真菌药物有效穿过血脑屏障并达到治疗相关浓度 中枢神经系统内的疾病将目前的治疗选择限制为三种药物：氟康唑、5-氟胞嘧啶和两性霉素。 流行菌株中对氟康唑和 5-氟胞嘧啶的耐药性水平的演变 隐球菌显着破坏了这些药物，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，有一个 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 抑制必需酶二氢叶酸还原酶（DHFR）的抗叶酸剂。尽管DHFR在临床上是一种 在几种真核病原体（例如恶性疟原虫和弓形虫）中经过验证的目标， 利用这一目标进行抗真菌药物开发的努力远远落后。 QMD 发现了一种新颖的 隐球菌抑制剂，其特点是具有高水平的抗真菌活性，同时具有初始剂量耐受性 药代动力学研究表明该化合物具有良好的特性，可以证明其体内功效 感染的动物模型。在这一阶段的应用中，我们将努力推进该项目的治疗 通过 (1) 抗菌谱分析、PK/PD 研究和阐明隐球菌感染机制 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) 在小鼠感染模型中评估先导化合物和备用化合物。证明的成功演示- 体内功效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。