Structural Biological Development of Fungal-Specific Calcineurin Inhibitors
真菌特异性钙调神经磷酸酶抑制剂的结构生物学发展
基本信息
- 批准号:9324801
- 负责人:
- 金额:$ 59.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-04 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:Antifungal AgentsAreaAspergillosisAspergillus fumigatusBindingBinding SitesBiochemicalBiologicalBiological AssayCalcineurinCalcineurin inhibitorCalmodulinCandida albicansCandidiasisCause of DeathCell divisionChemicalsChemistryClinicalCollaborationsCollectionComplexCoupledCrystallizationCrystallographyDNADevelopmentDiseaseDockingDrug TargetingDrug effect disorderEnzyme Inhibitor DrugsEnzymesFDA approvedFK506FoundationsGenerationsGeneticGenetic TranscriptionGrowthHIV Envelope Protein gp41HealthHumanImmune systemImmunityImmunocompromised HostImmunophilinsImmunosuppressionImmunosuppressive AgentsIn VitroIndustrial fungicideKnowledgeLeadMapsMedicalModificationMoldsMolecularMolecular TargetMutagenesisMycosesNMR SpectroscopyPPP3CA genePPP3CB genePathogenesisPathogenicityPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhenotypePhysiologyProductionProtein RegionProteinsResearchResistanceResistance developmentScreening ResultSignal TransductionSiteSite-Directed MutagenesisSpecificitySpicesStructural BiologistStructureSurfaceTacrolimus Binding Protein 1ATechniquesTestingThe science of MycologyTherapeuticTitrationsTranslatingTreatment EfficacyWorkYeastsanalogbasecalcineurin phosphataseclinical efficacycross reactivitydrug developmentexperimental studyfungusimmunogenicimprovedin vitro testinginhibitor/antagonistmouse modelnovelnovel strategiespathogenpublic health relevancesegregationstructural biology
项目摘要
DESCRIPTION (provided by applicant): Invasive fungal infections are a leading cause of death in immunocompromised patients. Current antifungals have limited clinical efficacy, are poorly fungicidal, are in some cases toxic, and are increasingly ineffective due to emerging resistance. We have established that the conserved phosphatase calcineurin is broadly required for invasive fungal disease. The FDA-approved calcineurin inhibitor FK506 is active in vitro against major invasive fungal pathogens, but also suppresses host immunity. Our approach seeks to overcome the fungal versus human specificity barrier to significantly advance antifungal treatment. The objective of this study is to utilize a structural biology-based strategy
to define fungal-mammalian calcineurin structural differences, validate fungal-specific targets, and generate and optimize novel FK506 analogs to treat invasive fungal diseases. Our central hypothesis is that by employing a structural biological approach using both crystallography and NMR spectroscopy that we will define novel targetable fungal-specific areas in the calcineurin complex critical for fungal pathogenesis. For maximum clinical breadth, we will focus on the two major clinical pathogens: the yeast Candida albicans and the mold Aspergillus fumigatus. Our preliminary studies document proof of principle non-immunosuppressive FK506 analogs with robust antifungal activity. We hypothesize that structures of the calcineurin A and B complex, coupled with calmodulin and the immunophilin complex (FKBP12-FK506), will reveal novel fungal-specific targets for inhibition. We have recently solved the structure for C. albicans, and will now solve structures for the calcineurin heterodimer alone and complexed with FKBP12-FK506/analogs from A. fumigatus. The multiple molecular views will allow identification of sites that are distinct between human and fungal calcineurin complexes that can be exploited for targeted inhibitor development. Protein regions that are dynamic or resist crystallization will be structurally characterized by NMR. Putative inhibitory domains will be validated via genetic and biochemical assays, utilizing site-directed mutagenesis of key contact and surface residues to examine structural stability, fungal phenotype, and drug action/resistance. Non-immunosuppressive fungal-specific FK506 analogs will be generated by Amplyx Pharmaceuticals based on the SAR results of our first iteration. This will guide the production of second generation analogs optimized for retention of antifungal activity and abrogation of immunosuppression by capitalizing on the unique structural differences between the host and fungal enzymes. Medicinal chemistry and inhibitor docking experiments will be conducted to alter analogs based on screening results. Lead compounds will be tested using an iterative approach both in vitro and in murine models of invasive candidiasis and invasive aspergillosis. We will capitalize on structural biology as a new approach to targeting calcineurin by defining fungal-specific features with no mammalian counterpart to generate novel antifungal therapeutics.
描述(由申请人提供):侵袭性真菌感染是免疫功能低下患者死亡的主要原因。目前的抗真菌药物临床疗效有限,杀真菌效果差,在某些情况下是有毒的,并且由于出现耐药性而越来越无效。我们已经确定保守的磷酸酶钙调磷酸酶在侵袭性真菌疾病中广泛需要。fda批准的钙调磷酸酶抑制剂FK506在体外对主要侵袭性真菌病原体有活性,但也抑制宿主免疫。我们的方法旨在克服真菌与人类特异性屏障,以显著推进抗真菌治疗。本研究的目的是利用结构生物学为基础的策略
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Forging the ring: from fungal septins' divergent roles in morphology, septation and virulence to factors contributing to their assembly into higher order structures.
锻造环:从真菌脓毒症在形态、分隔和毒力方面的不同作用,到有助于其组装成更高阶结构的因素。
- DOI:10.1099/mic.0.000359
- 发表时间:2016
- 期刊:
- 影响因子:0
- 作者:Vargas-Muñiz,JoseM;Juvvadi,PraveenR;Steinbach,WilliamJ
- 通讯作者:Steinbach,WilliamJ
FKBP12 dimerization mutations effect FK506 binding and differentially alter calcineurin inhibition in the human pathogen Aspergillus fumigatus.
FKBP12 二聚化突变影响 FK506 结合并差异改变人类病原体烟曲霉中钙调神经磷酸酶的抑制作用。
- DOI:10.1016/j.bbrc.2020.03.062
- 发表时间:2020
- 期刊:
- 影响因子:3.1
- 作者:Juvvadi,PraveenR;Bobay,BenjaminG;Gobeil,SophieMC;Cole,DChristopher;Venters,RonaldA;Heitman,Joseph;Spicer,LeonardD;Steinbach,WilliamJ
- 通讯作者:Steinbach,WilliamJ
An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens.
- DOI:10.1016/j.celrep.2015.10.018
- 发表时间:2015-11-17
- 期刊:
- 影响因子:8.8
- 作者:Robbins N;Spitzer M;Yu T;Cerone RP;Averette AK;Bahn YS;Heitman J;Sheppard DC;Tyers M;Wright GD
- 通讯作者:Wright GD
Characterization of the FKBP12-Encoding Genes in Aspergillus fumigatus.
- DOI:10.1371/journal.pone.0137869
- 发表时间:2015
- 期刊:
- 影响因子:3.7
- 作者:Falloon K;Juvvadi PR;Richards AD;Vargas-Muñiz JM;Renshaw H;Steinbach WJ
- 通讯作者:Steinbach WJ
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JOSEPH HEITMAN其他文献
JOSEPH HEITMAN的其他文献
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{{ truncateString('JOSEPH HEITMAN', 18)}}的其他基金
Malassezia and Candida auris: skin microbiome dysbiosis and de-regulation of cutaneous homeostasis
马拉色菌和耳念珠菌:皮肤微生物群失调和皮肤稳态失调
- 批准号:
10661959 - 财政年份:2023
- 资助金额:
$ 59.34万 - 项目类别:
RNAi-dependent epimutation roles in antimicrobial drug resistance and pathogenesis
RNAi 依赖性表突变在抗菌药物耐药性和发病机制中的作用
- 批准号:
10654857 - 财政年份:2022
- 资助金额:
$ 59.34万 - 项目类别:
Implications of mycoviral infection in Talaromyces marneffei: an analysis of human patient samples, RNAi, and hypermutation
马尔尼菲踝节菌中真菌病毒感染的影响:对人类患者样本、RNAi 和超突变的分析
- 批准号:
10191218 - 财政年份:2021
- 资助金额:
$ 59.34万 - 项目类别:
Implications of mycoviral infection in Talaromyces marneffei: an analysis of human patient samples, RNAi, and hypermutation
马尔尼菲踝节菌中真菌病毒感染的影响:对人类患者样本、RNAi 和超突变的分析
- 批准号:
10381581 - 财政年份:2021
- 资助金额:
$ 59.34万 - 项目类别:
The Genetic Basis of Virulence in Cryptococcus Neoformans
新型隐球菌毒力的遗传基础
- 批准号:
10658925 - 财政年份:2017
- 资助金额:
$ 59.34万 - 项目类别:
The Genetic Basis of Virulence in Cryptococcus Neoformans
新型隐球菌毒力的遗传基础
- 批准号:
10188404 - 财政年份:2017
- 资助金额:
$ 59.34万 - 项目类别:
The Genetic Basis of Virulence in Cryptococcus Neoformans
新型隐球菌毒力的遗传基础
- 批准号:
9389607 - 财政年份:2017
- 资助金额:
$ 59.34万 - 项目类别:
Structural Biological Development of Fungal-Specific Calcineurin Inhibitors
真菌特异性钙调神经磷酸酶抑制剂的结构生物学发展
- 批准号:
9113467 - 财政年份:2014
- 资助金额:
$ 59.34万 - 项目类别:
Structural Biological Development of Fungal-Specific Calcineurin Inhibitors
真菌特异性钙调神经磷酸酶抑制剂的结构生物学发展
- 批准号:
10248016 - 财政年份:2014
- 资助金额:
$ 59.34万 - 项目类别:
Structural Biological Development of Fungal-Specific Calcineurin Inhibitors
真菌特异性钙调神经磷酸酶抑制剂的结构生物学发展
- 批准号:
8745170 - 财政年份:2014
- 资助金额:
$ 59.34万 - 项目类别:
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