Antifungals targeting pantothenate phosphorylation

靶向泛酸磷酸化的抗真菌药

基本信息

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
项目类别：
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

项目摘要

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.

概括侵入性真菌感染（IFIS）创造了重要的医疗保健和经济伯恩斯，因为它们负责每年在全球范围内有超过10亿个感染，导致150万多人死亡。医院患者获得医院IFIS的人经历更长的医院，发病率增加和更高的死亡率。只有几类抗真菌药物可用，所有类别中的抗药性出现是对全球公共卫生的惊人威胁。特别关注的是由念珠菌，曲霉，曲霉引起的感染由于这些病原体和该病原体的抗性水平和肺炎囊肿相关的死亡率。迫切需要新的抗真菌群体，特别是随着出现多药耐药菌株的。为了满足这一需求，Curatix正在开发一种新的抗真菌群体破坏辅酶A（COA）生物合成的基本代谢途径和第一步泛素激酶（PANK）对维生素B5的磷酸化。遗传学研究证明在真菌中，此步骤对于细胞的生存能力至关重要，因此将真菌panks验证为出色的目标为了开发新的抗真菌药物。为了实现这一目标，我们进行了高通量〜156,593种化合物的屏幕以寻找烟曲霉的抑制剂，并确定了三个第一代单个化学型中的化合物，Ki值在190至360 nm之间。筛选和 86种类似物的初步医学化学优化，确定了四种第二代化合物，改善针对Afpank的活动以及酿酒酵母pank（CAB1），Ki值介于12至之间 CAB1的170 nm，Afpank的50 nm和217 nm。这些化合物对五个人没有细胞毒性细胞系，对人panks的真菌panks的选择性很高（EC50> 10 µm），以及显着的生物学在体外对白色念珠菌，副梭状芽胞杆菌和glabrata的活性。我们进一步解决了 CAB1作为Apo-酶，并与这些抑制剂复杂。这个阶段的计划将以这些为基础重要的数据具有评估体内这些铅化合物的生物学活性的目标启动SAR以提高其抗真菌效力（> 10倍）。在AIM 1中，我们将表征体内这些化合物在念珠菌病和曲霉病的动物模型中的功效。在AIM 2中，我们将建立在生物，生化和结构数据生成类似物的库，以识别具有针对多种真菌病原体的更多潜在活性。成功完成I阶段计划将提供支持II期计划所需的关键数据，该计划侧重于各种铅化合物的效率真菌感染的模型单独或与其他已知抗真菌抗体结合使用。 pank抑制剂的临床使用有可能为治疗IFI提供更有效的治疗选择，无论是单一疗法还是在与现有药物的结合，因此大大降低了与这些感染并改善患者的预后。