Directed Evolution of Selective Protease Inhibitors with an Expanded Genetic Code
具有扩展遗传密码的选择性蛋白酶抑制剂的定向进化
基本信息
- 批准号:8528629
- 负责人:
- 金额:$ 3.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-01 至 2014-03-29
- 项目状态:已结题
- 来源:
- 关键词:AcidsActive SitesAffinityAmberAmino AcidsAmino Acyl-tRNA SynthetasesAntibodiesArchitectureBacillus amyloliquefaciens ribonucleaseBacteriophagesBindingBoronic AcidsBreast Cancer CellCancer cell lineCapsid ProteinsCardiovascular DiseasesCell surfaceChloramphenicolConsensusCyclic PeptidesDNA SequenceDevelopmentDiagnosisDisulfidesEnzyme-Linked Immunosorbent AssayEstersEvolutionExtracellular DomainGenerationsGenetic CodeGenetic EngineeringGoalsHumanLabelLibrariesLigaseMalignant NeoplasmsMass Spectrum AnalysisMethanococcusMethodsMutateMutationNeoplasm MetastasisOrganismPeptide HydrolasesPeptide LibraryPeptide SynthesisPeptidesPhage DisplayPharmacologic SubstancePhasePhysiological ProcessesPopulationPost-Translational Protein ProcessingProtease InhibitorProteinsReagentRecombinantsScaffolding ProteinSerineSerine ProteaseSerine Proteinase InhibitorsSiteSolidSpecificitySystemTechniquesTechnologyTerminator CodonTestingTherapeutic InterventionTimeTissuesTransfer RNATranslatingTrypsinTyrosine-Specific tRNAbasecofactorcombinatorialdirected evolutionfitnessgel electrophoresisinhibitor/antagonistmatriptasemembermutantnovelnovel diagnosticsnovel therapeuticsoverexpressionpyrrolysinescreening
项目摘要
DESCRIPTION (provided by applicant): This proposal details the development of a general phage display selection strategy for evolving protein-based inhibitors that contain an unnatural amino acid "warhead" for selectively targeting cell surface proteases known to be overexpressed in cancer. All known organisms encode the same 20 amino acids. However, considering the vast array of cofactors and posttranslational modifications that endow endogenous proteins with altered functionalities, it is possible that an expanded genetic code may provide an evolutionary advantage through the generation of proteins with novel functions or enhanced fitness. It has recently been demonstrated that modified tRNAs and aminoacyl-tRNA synthetase pairs are capable of incorporating unnatural amino acids into large scale antibody libraries for the purpose of carrying out functional selections. Herein is described an initial phage display system for the incorporation of unnatural amino acids into cyclic peptide inhibitors of a cell surface protease, MT-SP1 (matriptase). The specific aims are as follows: 1) Genetically encoding an unnatural amino acid warhead for targeting the MT-SP1 active site and 2) Phage display of cyclic peptides for directed evolution using an expanded genetic code. Ultimately this strategy should be general for the directed evolution of unnatural amino acids in the context of peptides or larger protein scaffolds for targeting any relevant biomolecule.
描述(由申请人提供):该提案详细介绍了一种通用噬菌体展示选择策略的发展,该策略用于进化的基于蛋白质的抑制剂,该抑制剂含有非天然氨基酸“弹头”,用于选择性靶向已知在癌症中过表达的细胞表面蛋白酶。所有已知的生物体都编码相同的20种氨基酸。然而,考虑到大量的辅助因子和翻译后修饰使内源性蛋白质具有改变的功能,扩展的遗传密码可能通过产生具有新功能或增强适应性的蛋白质而提供进化优势。最近有研究表明,经过修饰的trna和氨基酰基- trna合成酶对能够将非天然氨基酸整合到大规模抗体文库中,以进行功能选择。本文描述了一种初始噬菌体展示系统,用于将非天然氨基酸掺入细胞表面蛋白酶MT-SP1(基质酶)的环肽抑制剂中。具体目的如下:1)基因编码一个针对MT-SP1活性位点的非天然氨基酸战斗部;2)利用扩展的遗传密码展示环状肽的噬菌体,用于定向进化。最终,这种策略应该适用于针对任何相关生物分子的肽或更大的蛋白质支架的非天然氨基酸的定向进化。
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)
A versatile platform for single- and multiple-unnatural amino acid mutagenesis in Escherichia coli.
- DOI:10.1021/bi4000244
- 发表时间:2013-03-12
- 期刊:
- 影响因子:2.9
- 作者:Chatterjee, Abhishek;Sun, Sophie B.;Furman, Jennifer L.;Xiao, Han;Schultz, Peter G.
- 通讯作者:Schultz, Peter G.
{{
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 }}
Jennifer L. Furman其他文献
Evaluation of the benefits of exercise on cognition in major depressive disorder.
评估运动对重度抑郁症认知的益处。
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:7
- 作者:
T. Greer;Jennifer L. Furman;M. Trivedi - 通讯作者:
M. Trivedi
Early Engineering Approaches to Improve Peptide Developability and Manufacturability
- DOI:
10.1208/s12248-014-9681-9 - 发表时间:
2014-10-23 - 期刊:
- 影响因子:3.700
- 作者:
Jennifer L. Furman;Mark Chiu;Michael J. Hunter - 通讯作者:
Michael J. Hunter
Differential prediction of antidepressant treatment response via measurement of baseline adiponectin level: findings from the CO-MED randomized clinical trial
- DOI:
10.1016/j.jad.2018.10.291 - 发表时间:
2019-07-01 - 期刊:
- 影响因子:
- 作者:
Jennifer L. Furman;Abigail Soyombo;Andrew H. Czysz;Manish K. Jha;Thomas J. Carmody;Brittany L. Mason;Philipp E. Scherer;Madhukar H. Trivedi - 通讯作者:
Madhukar H. Trivedi
Jennifer L. Furman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('Jennifer L. Furman', 18)}}的其他基金
Directed Evolution of Selective Protease Inhibitors with an Expanded Genetic Code
具有扩展遗传密码的选择性蛋白酶抑制剂的定向进化
- 批准号:
8325229 - 财政年份:2011
- 资助金额:
$ 3.35万 - 项目类别:
Directed Evolution of Selective Protease Inhibitors with an Expanded Genetic Code
具有扩展遗传密码的选择性蛋白酶抑制剂的定向进化
- 批准号:
8198219 - 财政年份:2011
- 资助金额:
$ 3.35万 - 项目类别:
相似海外基金
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:
$ 3.35万 - 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:
2334970 - 财政年份:2024
- 资助金额:
$ 3.35万 - 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:
$ 3.35万 - 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:
$ 3.35万 - 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:
$ 3.35万 - 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:
$ 3.35万 - 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:
$ 3.35万 - 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:
$ 3.35万 - 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:
$ 3.35万 - 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:
$ 3.35万 - 项目类别:
Discovery Grants Program - Individual