Development of Broad Spectrum Antifungal Agents
广谱抗真菌药物的开发
基本信息
- 批准号:9909111
- 负责人:
- 金额:$ 30万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAffectAgingAntibioticsAntifungal AgentsAntimetabolitesAreaAspergillus fumigatusAutoimmune DiseasesBacteriaBiochemicalBiological AssayBone Marrow TransplantationCandidaCandida albicansCandidiasisCell Culture TechniquesCellsCessation of lifeClinicalCommunicable DiseasesComputer AnalysisCryptococcus neoformansDataDescriptorDevelopmentDevelopment PlansDihydrofolate ReductaseDihydrofolate Reductase InhibitorDiseaseDrug resistanceDrug usageEnzymesEvaluationExhibitsFamilyFluconazoleFolic AcidFolic Acid AntagonistsFungal Drug ResistanceGoalsGrantGrowthHospitalsHumanImmunocompetentImmunocompromised HostImmunologicsIn VitroIncidenceIndividualInfectionInfectious AgentIntensive Care UnitsInternal MedicineIntestinesLaboratoriesLeadLifeLife ExpectancyMetabolicMolecularMulti-Drug ResistanceMycosesOperative Surgical ProceduresOpportunistic InfectionsOral cavityOral mucous membrane structureOrganOrganismPathogenicityPatientsPermeabilityPersonsPharmaceutical ChemistryPharmacologic SubstancePhasePopulationPositioning AttributePredispositionPrevalenceProductionPropertyQuercusResistanceResistant candidaRouteSepsisSeriesSkinSmall Business Technology Transfer ResearchSolidSolubilitySourceSpecificitySymptomsSystemic infectionTestingTherapeuticToxic effectUrinary tractUrinary tract infectionVirulenceVirulentWorkYeastsactive methodanalogbasecandidate selectioncandidemiachemotherapydesigndrug developmentdrug discoveryechinocandin resistanceefficacy testingexperiencefungushigh riskhuman pathogenimmunosuppressedinhibitor/antagonistlead candidatelead seriesmortalitynovelnovel therapeuticspathogenpathogenic funguspublic health relevancereproductive tractresistant strainscreeningsmall moleculetargeted treatmentward
项目摘要
ABSTRACT
Candidiasis is a fungal infection caused by yeasts that belong to the genus Candida. Candida yeasts normally
reside in the mouth, intestines and on the skin of all humans and do not pose an immediate threat to the average
immunocompetent person. However, Candida can cause opportunistic and frequently life-threatening conditions
in immunocompromised individuals or under conditions in which healthy bacteria levels are disrupted, especially
in hospital settings. Overall, Candida spp. are responsible for roughly 10% of all blood infections with a mortality
rate of 20-50%. The number of cases of invasive candidiasis is expected to rise with increased numbers of aging
and immunosuppressed individuals in the population. Numerous over-the-counter agents are available for
treating less severe symptoms of the skin and genital and urinary tracts; however, treatment options for systemic
infections are limited by toxicity of front line therapy and increasing rates of resistance. Although C. albicans has
historically been the most prominent Candida species, it is now recognized that other Candida species are
increasing in prevalence with C. albicans, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei considered the
most virulent. The highest rates of antifungal drug resistance are associated with C. glabrata, which is intrinsically
resistant to both common classes of antifungal agents, accounting for more than 70% of all echinocandin-
resistant isolates and over 90% of all multidrug-resistant isolates. We have formed a new start-up venture,
Quercus Molecular Design (QMD LLC), whose long-term objective is to identify, characterize, and exploit
infectious disease drug targets for the treatment of the immunologically vulnerable. Since DHFR is highly
conserved among fungal species, fungi-specific folate antimetabolites are anticipated to have broad spectrum
activity against multiple Candida species. We hypothesize that it will be possible to develop dihydrofolate
reductase (DHFR) inhibitors that inhibit multiple Candida species. This phase I proposal is based on exciting
preliminary data indicating that small molecule lead compounds exhibit high levels of specificity for the fungal
DHFR enzyme over the human counterpart and also exhibit excellent antifungal activity against C. albicans and
C. glabrata. The purpose of this Phase 1 STTR is to determine the feasibility of developing a broadly active
treatment for multiple species of Candida. To that end, efficacy of the lead series will be evaluated against
isolates of Candida spp., including drug-resistant strains and the lead series will be expanded through a focused
medicinal chemistry effort and tested for efficacy in vitro and in cell culture. This phase I proposal is based on a
decade of work from Dr. Dennis Wright’s laboratory focused on small-molecule drug discovery in infectious
disease. This proposal also leverages Dr. Lee Wright’s nearly 20 years of experience in the areas of
pharmaceutical medicinal chemistry and small-molecule drug development and Dr. Michael Cynamon’s multiple
decades of clinical work in the identification, evaluation and treatment of fungal disease. Our long-term goal is
to develop the most promising lead compounds to create a broadly-acting Candida therapeutic.
摘要
念珠菌病是一种由念珠菌属酵母菌引起的真菌感染。念珠菌酵母通常
存在于所有人的口腔、肠道和皮肤上,对一般人不构成直接威胁。
免疫力强的人。然而,念珠菌可导致机会性和经常危及生命的条件
在免疫功能低下的个体中或在健康细菌水平被破坏的条件下,特别是
在医院里总体而言,念珠菌属(Candida spp.)大约占所有血液感染的10%,
率为20 - 50%。侵袭性念珠菌病的病例数预计将随着老龄化人数的增加而增加。
和免疫抑制的个体。许多非处方药可用于
治疗不太严重的皮肤、生殖器和泌尿道症状;然而,
感染受到一线治疗的毒性和增加的耐药率的限制。虽然C.白色念珠菌具有
历史上是最突出的念珠菌属物种,现在认识到其他念珠菌属物种是
随着C.白色念珠菌、C.光叶C. tropicalis、热带假丝酵母C. parapsilosis和C.克鲁塞伊认为,
最致命的抗真菌药物耐药率最高的是C。glabrata,本质上是
对两种常见的抗真菌药物都有耐药性,占所有棘白菌素的70%以上,
耐药菌株和超过90%的多重耐药菌株。我们成立了一家新的创业公司
Quercus Molecular Design(QMD LLC),其长期目标是识别、表征和开发
传染病药物的目标是治疗免疫脆弱的人。由于DHFR高度
在真菌物种中保守,真菌特异性叶酸抗代谢物预期具有广谱
对多种念珠菌属的活性。我们假设有可能开发出二氢叶酸
还原酶(DHFR)抑制剂,其抑制多种念珠菌属物种。第一阶段的建议是基于令人兴奋的
初步数据表明,小分子先导化合物对真菌表现出高水平的特异性,
DHFR酶的活性高于人DHFR酶,并且对C.白色念珠菌和
C.光滑的本第1阶段STTR的目的是确定开发广泛活跃的
治疗多种念珠菌。为此,将评价电极导线系列的有效性,
念珠菌属的分离物,包括耐药菌株和铅系列将扩大通过一个重点
药物化学的努力,并在体外和细胞培养中测试功效。第一阶段的建议是基于一个
丹尼斯·赖特博士实验室的十年工作集中在感染性疾病的小分子药物发现上。
疾病该提案还利用了Lee Wright博士在以下领域近20年的经验:
药物药物化学和小分子药物开发和迈克尔Cynamon博士的多个
数十年的临床工作,在鉴定,评估和治疗真菌疾病。我们的长期目标是
开发最有前途的先导化合物,以创造一种广泛作用的念珠菌治疗剂。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Dennis L. Wright其他文献
Dennis L. Wright的其他文献
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{{ truncateString('Dennis L. Wright', 18)}}的其他基金
Therapeutic Agents Targeting Cryptococcal Infections
针对隐球菌感染的治疗药物
- 批准号:
10697960 - 财政年份:2023
- 资助金额:
$ 30万 - 项目类别:
New Agents for the Treatment on Mycobacteria Avium Infections
治疗鸟分枝杆菌感染的新药
- 批准号:
10597233 - 财政年份:2022
- 资助金额:
$ 30万 - 项目类别:
New Agents for the Treatment on Mycobacteria Avium Infections
治疗鸟分枝杆菌感染的新药
- 批准号:
10482476 - 财政年份:2022
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$ 30万 - 项目类别:
Propargyl-linked Antifolates Targeting Klebsiella pneumoniae
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9178633 - 财政年份:2013
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8960331 - 财政年份:2013
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8089567 - 财政年份:2006
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