Developing Synthetic Enzymes to Treat Inborn Errors of Metabolism
开发合成酶来治疗先天性代谢缺陷
基本信息
- 批准号:10540317
- 负责人:
- 金额:$ 15.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-13 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdolescentAdultAmino AcidsAmino Acids ActivationAmmoniaAnabolismAnimalsBiochemistryBranched-Chain Amino AcidsCaregiversChildChronicClinicalComputer AnalysisComputer ModelsComputer SimulationDataDeaminationDescriptorDevelopmentDietDirected Molecular EvolutionDiseaseDistalDrug KineticsEngineeringEnzymesFamilyFormulationFoundationsFunding MechanismsGoalsGrantInborn Errors of MetabolismIndividualInfantInfectionInjectableIsoleucineKeto AcidsKineticsLeadLeucineLibrariesLyaseMaple Syrup Urine DiseaseMetabolicMetabolismModalityModelingMonitorMutagenesisMutationNatureNeurologicNewborn InfantNutrientOutcomeOxidoreductasePathologyPathway interactionsPatientsPharmaceutical PreparationsPharmacodynamicsPhenylalaninePhenylalanine Ammonia-LyasePhenylketonuriasProbabilityPropertyProtein EngineeringProtein-Restricted DietQuality of lifeQuantum MechanicsReactionResidual stateResolutionSiteSupplementationSystemTechniquesTechnologyTestingThermodynamicsToxic effectValineVariantWorkamino acid therapycofactordesigndietary restrictionenzyme activityenzyme modelenzyme replacement therapyenzyme substrate complexhigh throughput screeningimprovedinnovationisovaleric acidemiamolecular mechanicsnovelprogramsrisk mitigationsimulationsuccesssynthetic enzymetherapeutic developmenttranslational potential
项目摘要
Project Summary.
The severe, acute, and chronic developmental and neurological impacts seen in branched chain ketoacid
dehydrogenase deficient Maple Syrup Urine Disease (BCKD-deficient MSUD) and isovaleryl‐CoA
dehydrogenase deficient Isovaleric Acidemia (IVD-deficient IVA) seen in newborns are due to the presence of
high concentrations of leucine, isoleucine, and valine in their system. Patients with these disorders are limited
to manage their condition though a low-protein diet and nutrient supplementation, which is often inadequate,
difficult to adhere to, and can still lead to metabolic decompensation. Management strategies include reduction
and restriction of toxic metabolites and substrates, promotion of anabolism and stimulation of residual enzyme
activity along with activation of amino acid and ketoacid scavenging pathways. Even then, the quality of life of
patients is poor, as is for their caregivers since patients need to be monitored closely to avoid metabolic crisis
precipitated either by infection, diet, or other reasons. Thus, there is significant need for new medications that
can benefit infants, children, adolescents, and adults. This work is based on the hypothesis that high systemic
concentrations of offending amino acid(s) in patients can be reduced using high activity enzymes, in a manner
like how Pegvaliase reduces phenylalanine concentrations in phenylketonuria (PKU) patients. Core to this work
is implementation of a twofold approach that combines experimental directed evolution techniques and
computations enzyme design.
项目摘要。
支链酮酸对发育和神经的严重、急性和慢性影响
脱氢酶缺陷性枫糖浆尿病与异戊酰辅酶A
新生儿脱氢酶缺陷性异戊酸血症(IVD缺陷性IVA)是由于存在
它们的体内含有高浓度的亮氨酸、异亮氨酸和缬氨酸。患有这些疾病的患者是有限的
通过低蛋白质饮食和营养补充来管理他们的状况,这通常是不够的,
很难坚持,而且仍然可能导致代谢失调。管理策略包括减少
以及限制有毒代谢物和底物,促进合成代谢和刺激残留酶
活性以及激活氨基酸和酮酸清除途径。即使到了那时,中国人的生活质量
病人很穷,他们的照顾者也是如此,因为病人需要被密切监测以避免代谢危机
由感染、饮食或其他原因引起的。因此,对新药的需求非常大。
可使婴儿、儿童、青少年和成年人受益。这项工作是基于这样一个假设,即高度系统性
在某种程度上,使用高活性的酶可以降低患者体内有害氨基酸(S)的浓度
比如Pegvaliase如何降低苯丙酮尿症(PKU)患者的苯丙氨酸浓度。这项工作的核心
是一种双重方法的实现,它结合了实验性的定向进化技术和
计算酶设计。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Towards universal synthetic heterotrophy using a metabolic coordinator.
使用代谢协调器实现通用合成异养。
- DOI:10.1016/j.ymben.2023.07.001
- 发表时间:2023
- 期刊:
- 影响因子:8.4
- 作者:Sullivan,SeanF;Shetty,Anuj;Bharadwaj,Tharun;Krishna,Naveen;Trivedi,VikasD;EndalurGopinarayanan,Venkatesh;Chappell,ToddC;Sellers,DanielM;PravinKumar,R;Nair,NikhilU
- 通讯作者:Nair,NikhilU
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Nikhil Unni Nair其他文献
Nikhil Unni Nair的其他文献
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{{ truncateString('Nikhil Unni Nair', 18)}}的其他基金
Developing Synthetic Enzymes to Treat Inborn Errors of Metabolism
开发合成酶来治疗先天性代谢缺陷
- 批准号:
10281241 - 财政年份:2021
- 资助金额:
$ 15.37万 - 项目类别:
Toward Altered Probiotic Therapy for Phenylketonuria
改变苯丙酮尿症的益生菌疗法
- 批准号:
9227238 - 财政年份:2017
- 资助金额:
$ 15.37万 - 项目类别:
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