Biochemical Strategy to Avert Microbial Drug Resistance
避免微生物耐药性的生化策略
基本信息
- 批准号:10510991
- 负责人:
- 金额:$ 26.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-14 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVActive SitesAmino Acid SequenceAntiviral AgentsBiochemicalCause of DeathCellsClinicalCommunicable DiseasesCytotoxinEnzyme PrecursorsEnzymesEquus caballusGenomeGoalsHumanLinkLungMediatingMicrobial Drug ResistanceModelingPathogenicityPatientsPeptide HydrolasesPeriodicityProdrugsProteinsRNARNA SplicingRNA VirusesResearchResistanceRibonucleasesSARS-CoV-2 proteaseSpecificitySystemVariantViral reservoirVirusantimicrobialcatalystcytotoxicfrontierinfectious disease treatmentinteinmicrobialmicrobial diseasepathogenpathogenic microbepublic health relevanceresistance mechanism
项目摘要
PROJECT SUMMARY/ABSTRACT
The goal of the proposed research is to develop a generalizable antimicrobial strategy
that averts the onset of resistance. The proposed antiviral agent has a mechanism of
action that relies on the function of a pathogenic protein rather than its inhibition.
Specifically, the agent is a cytotoxic variant of a human enzyme, ribonuclease 1
(RNase 1), that is cloaked and thus inactive as a catalyst. The cloak is removable only by
a pathogenic protease that is essential for the lifecycle of the pathogen. SARS-CoV-2 will
serve as a model pathogen in the study. The goal will be attained by (1) identifying an
optimal amino acid sequence that is cleaved by the 3CLpro protease of SARS-CoV-2 but
not by endogenous human proteases, (2) using that sequence and intein-mediated cis-
splicing to create a cyclic RNase 1 zymogen, and (3) demonstrating the ability of the
zymogen to kill human lung cells that express 3CLpro and that are infected by
SARS-CoV-2. Because the activated zymogen can also destroy the genome of an RNA
virus like SARS-CoV-2, it could eradicate the viral reservoir in patients. A notable feature
of the strategy is its modularity: the protease-cleavage sequence is a cassette that can be
altered to match the specificity of pathogenic proteases for the treatment of other
infectious diseases.
项目摘要/摘要
拟议研究的目标是开发一种可推广的抗菌策略。
这避免了耐药性的发生。建议的抗病毒药物的机制是
依赖于致病蛋白质的功能而不是其抑制作用的作用。
具体地说,该试剂是一种人体酶的细胞毒性变体,核糖核酸酶1
(核糖核酸酶1),它是被遮盖的,因此作为催化剂没有活性。斗篷只有通过以下方式才能取下
在病原体的生命周期中必不可少的一种致病蛋白酶。SARS-CoV-2将
在这项研究中作为模型病原体。该目标将通过(1)确定一个
SARS-CoV-2 3CLPro酶切割BUT的最佳氨基酸序列
不是通过内源性的人蛋白酶,(2)使用该序列和内含素介导的顺式-
剪接以创建环RNase1酶原,以及(3)展示了
酶原杀死表达3CLPro并感染3CLPro的人肺细胞
SARS-CoV-2。因为被激活的酶原也会破坏RNA的基因组
像SARS-CoV-2这样的病毒,它可以根除患者的病毒库。一个显著的特点
这一策略的特点是它的模块化:蛋白酶裂解序列是一个盒式磁带,可以
改变以匹配致病蛋白酶治疗其他疾病的特异性
传染病。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ronald T Raines其他文献
Hydrolytic Stability of Hydrazones and Oximes** Hydrazones and Oximes (c
腙和肟的水解稳定性** 腙和肟 (c
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
J. Kalia;Ronald T Raines;J. Kalia;R T Raines;R T Raines;W. W. F. Cleland;Nelsen;T. J. Shoulders;Rutkoski - 通讯作者:
Rutkoski
n→π* interactions in proteins
蛋白质中的 n→π* 相互作用
- DOI:
10.1038/nchembio.406 - 发表时间:
2010-07-11 - 期刊:
- 影响因子:13.700
- 作者:
Gail J Bartlett;Amit Choudhary;Ronald T Raines;Derek N Woolfson - 通讯作者:
Derek N Woolfson
Jeremy R. Knowles (1935-2008).
杰里米·R·诺尔斯 (1935-2008)。
- DOI:
10.1021/cb800099n - 发表时间:
2008 - 期刊:
- 影响因子:4
- 作者:
Ronald T Raines - 通讯作者:
Ronald T Raines
Ronald T Raines的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ronald T Raines', 18)}}的其他基金
Biochemical Strategy to Avert Microbial Drug Resistance
避免微生物耐药性的生化策略
- 批准号:
10645218 - 财政年份:2022
- 资助金额:
$ 26.41万 - 项目类别:
Esterase Specificity for Pharmacology and Chemical Biology
药理学和化学生物学的酯酶特异性
- 批准号:
10017292 - 财政年份:2019
- 资助金额:
$ 26.41万 - 项目类别:
TRAINING IN THE USE OF BRUKER AND VARIAN SPECTROMETERS AND NMR
布鲁克和瓦里安光谱仪和核磁共振的使用培训
- 批准号:
8361163 - 财政年份:2011
- 资助金额:
$ 26.41万 - 项目类别:
ROUTINE NMR FOR CHARCATERIZATION OF ORGANIC CHEMICALS
用于表征有机化学品的常规 NMR
- 批准号:
8361152 - 财政年份:2011
- 资助金额:
$ 26.41万 - 项目类别:
DETERMINATION OF INTERACTIONS BETWEEN RIBONUCLEASE 1 AND CHEMICAL LIGANDS
核糖核酸酶 1 和化学配体之间相互作用的测定
- 批准号:
8361216 - 财政年份:2011
- 资助金额:
$ 26.41万 - 项目类别:
NMR INVESTIGATIONS BY THE RAINES LABORATORY 2
由 Raines 实验室进行的 NMR 研究 2
- 批准号:
8361217 - 财政年份:2011
- 资助金额:
$ 26.41万 - 项目类别:
TRAINING IN THE USE OF BRUKER AND VARIAN SPECTROMETERS AND NMR
布鲁克和瓦里安光谱仪和核磁共振的使用培训
- 批准号:
8168959 - 财政年份:2010
- 资助金额:
$ 26.41万 - 项目类别:
ROUTINE NMR FOR CHARACTERIZATION OF ORGANIC COMPOUNDS
用于表征有机化合物的常规 NMR
- 批准号:
8168934 - 财政年份:2010
- 资助金额:
$ 26.41万 - 项目类别:
相似海外基金
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334970 - 财政年份:2024
- 资助金额:
$ 26.41万 - 项目类别:
Standard Grant
NSF-BSF: Towards a Molecular Understanding of Dynamic Active Sites in Advanced Alkaline Water Oxidation Catalysts
NSF-BSF:高级碱性水氧化催化剂动态活性位点的分子理解
- 批准号:
2400195 - 财政年份:2024
- 资助金额:
$ 26.41万 - 项目类别:
Standard Grant
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334969 - 财政年份:2024
- 资助金额:
$ 26.41万 - 项目类别:
Standard Grant
Mechanochemical synthesis of nanocarbon and design of active sites for oxygen reducton/evolution reactions
纳米碳的机械化学合成和氧还原/演化反应活性位点的设计
- 批准号:
23K04919 - 财政年份:2023
- 资助金额:
$ 26.41万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Creation of porous inorganic frameworks with controlled structure of metal active sites by the building block method.
通过积木法创建具有金属活性位点受控结构的多孔无机框架。
- 批准号:
22KJ2957 - 财政年份:2023
- 资助金额:
$ 26.41万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Catalysis of Juxaposed Active Sites Created in Nanospaces and Their Applications
纳米空间中并置活性位点的催化及其应用
- 批准号:
23K04494 - 财政年份:2023
- 资助金额:
$ 26.41万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Generation of carbon active sites by modifying the oxygen containing functional groups and structures of carbons for utilizing to various catalytic reactions.
通过修饰碳的含氧官能团和结构来产生碳活性位点,用于各种催化反应。
- 批准号:
23K13831 - 财政年份:2023
- 资助金额:
$ 26.41万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
CAREER: CAS: Understanding the Chemistry of Palladium and Silyl Compounds to Design Catalyst Active Sites
职业:CAS:了解钯和甲硅烷基化合物的化学性质以设计催化剂活性位点
- 批准号:
2238379 - 财政年份:2023
- 资助金额:
$ 26.41万 - 项目类别:
Continuing Grant
CAS: Collaborative Research: Tailoring the Distribution of Transient vs. Dynamic Active Sites in Solid-Acid Catalysts and Their Impacts on Chemical Conversions
CAS:合作研究:定制固体酸催化剂中瞬时活性位点与动态活性位点的分布及其对化学转化的影响
- 批准号:
2154399 - 财政年份:2022
- 资助金额:
$ 26.41万 - 项目类别:
Standard Grant
Engineering of Active Sites in Heterogeneous Catalysts for Sustainable Chemical and Fuel Production.
用于可持续化学和燃料生产的多相催化剂活性位点工程。
- 批准号:
RGPIN-2019-06633 - 财政年份:2022
- 资助金额:
$ 26.41万 - 项目类别:
Discovery Grants Program - Individual