Antifungals targeting pantothenate phosphorylation

靶向泛酸磷酸化的抗真菌药

• 批准号: 10696567
• 负责人: Jae-Yeon Choi
• 金额: $ 29.4万
• 依托单位: CURATIX, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696567
• 关键词: Address; Amphotericin B; Anabolism; Animal Model; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Azoles; Binding; Biochemical; Biological; Candida; Candida albicans; Candidiasis; Catalytic Domain; Cell Survival; Cessation of life; Chemicals; Clinical; Coenzyme A; Complex; Cryptococcus; Data; Development; Disseminated candidiasis; Dose; Drug Kinetics; Drug resistance; Economic Burden; Economics; Enzymes; Ergosterol; Fluconazole; Generations; Genetic study; Goals; Healthcare; Hospitals; Human; Human Cell Line; Immunocompromised Host; In Vitro; Infection; Lead; Length of Stay; Libraries; Manuscripts; Maps; Metabolic; Metabolic Pathway; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mycoses; Nosocomial Infections; Oral; Organism; Pantothenate kinase; Pantothenic Acid; Pathway interactions; Patient-Focused Outcomes; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology Study; Phase; Phosphorylation; Pneumocystis; Polyenes; Property; Public Health; Regimen; Relationship-Building; Resistance; Saccharomyces cerevisiae; Safety; Solubility; Structure; Structure-Activity Relationship; United States; Vitamins; analog; care burden; cofactor; cytotoxicity; effective therapy; efficacy evaluation; experience; fungus; high throughput screening; improved; in vitro activity; in vivo; indexing; inhibitor; kinase inhibitor; lead candidate; meter; monomer; mortality; mouse model; novel; novel drug class; pathogen; pathogenic fungus; pharmacologic; programs; research and development; resistant strain; scaffold; screening; therapeutically effective; treatment strategy

SUMMARY Invasive fungal infections (IFIs) create significant healthcare and economic burdens as they are responsible for more than one billion infections worldwide each year resulting in more than 1.5 million deaths. Hospital patients who acquire nosocomial IFIs experience longer hospital stays, increased morbidity, and higher mortality rates. Only a few classes of antifungal drugs are available, and the emergence of resistance within all classes is an alarming threat to global public health. Of particular concern are infections caused by Candida, Aspergillus, Cryptococcus, and Pneumocystis species due the level of resistance seen with these pathogens and the associated mortality rates. New classes of anti-fungals are desperately needed, particularly with the emergence of multidrug resistant strains. To address this need, Curatix is developing a new class of anti-fungals that disrupt an essential metabolic pathway and first step in coenzyme A (CoA) biosynthesis - the phosphorylation of vitamin B5 by pantothenate kinase (PanK). Genetic and pharmacological studies demonstrated that in fungi, this step is essential for cell viability, thus validating fungal PanKs as excellent targets for the development of new classes of antifungal drugs. To achieve this goal, we conducted high-throughput screen of ~156,593 compounds to search for inhibitors of A. fumigatus AfPanK and identified three 1st generation compounds within a single chemotype with Ki values ranging between 190 and 360 nM. Screening and preliminary medicinal chemistry optimization of 86 analogs identified four 2nd generation compounds with improved activity against AfPanK as well as S. cerevisiae PanK (Cab1) with Ki values ranging between 12 and 170 nM for Cab1 and 50 and 217 nM for AfPanK. The compounds showed no cytotoxicity against five human cell lines, very high selectivity for fungal PanKs over human PanKs (EC50 >10 µM), and significant biological activity in vitro against C. albicans, C. parapsilosis and C. glabrata. We further solved the crystal structure of Cab1 as an apo-enzyme and in complex with these inhibitors. This Phase I program will build upon these significant data with the goal to evaluate the biological activity of these lead compounds in vivo and initiate an SAR to improve their antifungal potency (>10 fold). In Aim 1 we will characterize the in vivo efficacy of these compounds in animal models of candidiasis and aspergillosis. In Aim 2, we will build upon the biological, biochemical and structural data to generate a library of analogs in order to identify compounds with more potent activity against multiple fungal pathogens. Successful completion of the Phase I program will provide the critical data needed to support a Phase II program focused on the efficacy of the lead compounds in various models of fungal infections alone or in combination with other known antifungals. Clinical use of a PanK inhibitor has the potential to provide a more effective therapeutic option for treating IFIs, both as monotherapy and in combination with existing drugs, thus greatly decreasing the economic and healthcare burdens associated with these infections and improving patient outcomes.

摘要 侵袭性真菌感染(IFI)造成巨大的医疗和经济负担，因为它们负责 全世界每年有10多亿人感染，导致150多万人死亡。住院病人 感染医院感染的患者住院时间更长，发病率更高，死亡率更高。 只有几类抗真菌药物可用，所有类别中出现抗药性是一种 对全球公共卫生的令人震惊的威胁。尤其令人担忧的是由念珠菌、曲霉、 隐球菌和肺孢子虫由于对这些病原体的抗药性水平以及 相关死亡率。迫切需要新的抗真菌药物，特别是随着 耐多药菌株。为了满足这一需求，Curatix正在开发一种新的抗真菌药物 破坏辅酶A(CoA)生物合成的基本代谢途径和第一步- 泛酸激酶(Pank)对维生素B5的磷酸化作用。遗传学和药理学研究 证明在真菌中，这一步骤对细胞存活是必不可少的，从而证实真菌Pank是极好的靶标。 用于开发新型抗真菌药物。为了实现这一目标，我们进行了高吞吐量 从156,593个化合物中筛选烟曲霉菌抑制物并鉴定出3个第一代 KI值在190到360 nm之间的单一化学类型中的化合物。筛选和 86个类似物的初步药用化学优化 提高了对AfPanK和S.cerevisiae Pank(Cab1)的活性，Ki值在12到12之间 CAB1为170 NM，AfPanK为50和217 NM。这些化合物对五个人没有细胞毒性。 细胞系，对真菌Pank的选择性高于人类Pank(EC50和GT；10微米)，以及显著的生物学意义 体外抗白色念珠菌、近缘念珠菌和光滑念珠菌的活性。我们进一步解决了它的晶体结构。 CAB1作为一种脱辅酶，与这些抑制剂形成复合体。该第一阶段计划将建立在这些基础上 重要数据，目的是评估这些先导化合物在体内的生物活性 启动SAR以提高其抗真菌效力(&gt；10倍)。在目标1中，我们将描述体内的 这些化合物在念珠菌病和曲霉病动物模型中的疗效。在目标2中，我们将在 生物、生化和结构数据，以生成类似物库，以便与 对多种真菌病原体具有更强的活性。成功完成第一阶段计划将提供 支持第二阶段计划所需的关键数据侧重于先导化合物在各种环境中的功效 单独或与其他已知抗真菌药物联合使用的真菌感染模型。PANK抑制剂的临床应用 有可能为治疗IFI提供更有效的治疗选择，无论是作为单一疗法还是在 与现有药物相结合，从而极大地减轻了与 这些感染和改善患者的预后。