权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of a new class of antifungals effective against Cryptococcus

开发一类有效对抗隐球菌的新型抗真菌药

基本信息

批准号：
10092096
负责人：
Marc Sharp
金额：
$ 71.46万
依托单位：
LINNAEUS BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-12 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092096
关键词：
3-Dimensional Amphotericin B Animal Model Antifungal Agents Antifungal Therapy Aspergillosis Aspergillus Bioavailable Biological Assay Biological Availability Biological Sciences Brain CD69 antigen Candida Candidiasis Cell Wall Cryptococcal Meningitis Cryptococcus Cryptococcus gattii Cryptococcus neoformans Cytochrome P450 Data Development Disease Drug usage Effectiveness Ensure Enzymes Fluconazole Flucytosine Formulation Fungal Proteins GPI Membrane Anchors Genetic Epistasis Goals Homologous Gene Human Immunocompromised Host In Situ In Vitro Individual Infection Inhalation Intravenous Investigation Left Life Liposomes Lung Lung infections Maximum Tolerated Dose Metabolic Methods Microbiology Microscopy Modeling Molds Mus Mutation Mycoses Neoadjuvant Therapy Neuraxis Oral Outcome Patient-Focused Outcomes Pharmacologic Substance Phase Phase I Clinical Trials Phenotype Prodrugs Protein Isoforms Proteins Regimen Reporting Resistance Resources Risk Safety Sterilization Structure of parenchyma of lung Technology Testing Therapeutic Therapeutic Agents Tissues Toxic effect Transferase Treatment outcome Universities analog animal efficacy base burden of illness clinical development clinical practice cytotoxicity deoxycholate effective therapy efficacy evaluation efficacy study fungus improved in vitro activity in vivo infection burden inhibitor/antagonist medical schools mortality mouse model novel novel therapeutics optimal treatments pathogen pathogenic fungus phase II trial resistance frequency resistant strain scale up standard of care synergism

项目摘要

Goal: To create a well-tolerated, orally available therapeutic that can be employed alone or in combination with other antifungal agents to improve treatment outcomes for patients suffering from cryptococcal meningitis (CM). The worldwide disease burden of infections caused by Cryptococcus is over one million cases annually. The disease is normally caused by inhalation of the fungus, which spreads from the lungs to the central nervous system in immunocompromised individuals, where it is classified as cryptococcal meningitis (CM). CM is always fatal if left untreated. First-line therapy is limited to amphotericin B/5- flucytosine, which is largely unavailable in the developing world. Our recent efforts to identify novel therapeutics to treat CM have focused on targeting the fungal protein Gwt1 acyl transferase, an enzyme that is required for the assembly of glycosylphosphatidylinositol (GPI) anchored proteins that are later attached to the fungal cell wall. Amplyx Pharmaceuticals has in-licensed a portfolio of potent Gwt1 inhibitors from Eisai, including APX001, the first-on-class molecule which has completed Phase 1 clinical trials. APX001A, the active moiety of APX001, has some activity against Cryptococcus, however, its potency in mouse animal models is best observed in combination with fluconazole. We have recently synthesized and evaluated additional Gwt1 inhibitors and have identified several molecules with significantly improved microbiological activity (> 30-fold) against C. neoformans and C. gattii. In this proposal, Linnaeus Bioscience Inc. will develop a microscopy based assay for C. neoformans and use it to confirm that the new molecules target Gwt1, evaluate synergy with other antifungal agents, and explore in vitro and in vivo phenotypic effects. Dr. John Perfect, Duke University School of Medicine, will evaluate compounds for efficacy in mouse models of CM. The ultimate outcome of this proposal will be the selection of a candidate for IND-enabling studies that demonstrates a significant improvement vs APX001 in both CM survival and fungal burden mouse models. We will begin by developing a rapid microscopy assay for determining the mechanism of action (MOA) of Gwt1 inhibitors in Cryptococcus and apply it to studies of APX001A analogs. We will then characterize 30 analogs of APX001A molecules that are significantly more potent (4 to >32 fold) than APX001A vs Cryptococcus. We plan to use our new microscopy based assay to ensure these more potent molecules are on target. We will also characterize these molecules for their potential cytotoxicity and metabolic stability. The top 10 compounds will be selected and further studied to characterize their microbiological activities, including determining their spectrum of activity against a panel of C. neoformans and C. gattii isolates. We will successfully scale-up the synthesis of 8-10 selected analogs in prodrug form and assess appropriate formulations for use in animal efficacy studies. We will characterize the PK, MTD and safety for 8-10 compounds, identifying molecules with over 40% oral bioavailability that have an MTD, potential for hERG inhibition, and potential for cytochrome P450 isoform interaction that is equivalent to or better than APX001 (APX001A). In the final step, we will demonstrate the efficacy of 5-10 compounds in Cryptococcus neoformans animal models of infection. We will test molecules for their ability to reduce fungal burden in lung and brain models and to improve survival in CM models. We will also determine if these compounds reduce fungal burden when used in combination with fluconazole (or other antifungals that are used for the treatment of CM). We will use our microscopy based assay to assess Gwt1 inhibitor effectiveness and mode of action in vivo in brain and lung infection models. When completed we will declare a candidate ready for IND enabling studies.

目标：创造一种耐受性良好，可口服的治疗药物，可单独使用或用于