Exploring the Limits of Ribosome Mediated Polymerizations for Expanding the Genetic Code
探索核糖体介导的聚合对扩展遗传密码的限制
基本信息
- 批准号:10350599
- 负责人:
- 金额:$ 2.08万
- 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:2021-01-25 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcylationAddressAffectAmidesAmino AcidsBiological ProductsBiopolymersBiotechnologyCatalysisChargeChemistryDevelopmentDiabetes MellitusEscherichia coliEstersExhibitsExposure toFellowshipGenetic CodeGenetic TranscriptionGoalsHealthHumanIn VitroIndividualInsulinInterdisciplinary StudyLibrariesLifeMediatingMedicineMethodsModelingMolecularMonoclonal AntibodiesNylonsPeptidesPhysical condensationPolymersProceduresProductionProteinsPyrazolonesRecombinant ProteinsRecombinantsResearchRibosomesSavingsSchemeSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationStructureSystemTechnologyTherapeuticTransfer RNATranslationsTreatment EfficacyUniversitiesVertebral columnWorkWorld Health Organizationdesignexperimental studyinnovationmedical specialtiesmonomernovelpeptide drugpolymerizationpolypeptidescaffoldsynthetic biologytherapeutic proteintool
项目摘要
PROJECT SUMMARY
Recombinant protein production (RPP) has become a powerful tool for producing life-saving
therapeutics such as insulin, monoclonal antibodies, and other critical biopharmaceuticals. However, this
promising technology is severely limited by the ability to efficiently expand the genetic code to incorporate
exotic monomers and backbones for enhanced therapeutic function. The vast majority of biopolymers currently
produced by the translation machinery display polyamide backbones; therefore, the possible secondary and
tertiary confirmations available to proteomimetics synthesized via RPP are limited to these scaffolds. Since
monomer sequence defines structure and structure defines function, expanding the available monomer pool for
translation will produce biopolymers with greater structural complexity and thus increase the functional
capabilities for proteomimetic therapeutics. A major limitation to addressing this issue is the underexplored
capability of the ribosome to incorporate unnatural monomers, especially those that do not form peptide
(amide) bonds. Toward this goal, this proposal aims to develop genetically encoded chemistries that can be
catalyzed by the ribosome to synthesize sequence defined polymers (SDPs) with structurally diverse
backbones (non-peptide bonds).
Specifically, I will design and synthesize a library of a-hydrazino-keto ester monomers, charge them
onto orthogonal tRNA, introduce them to the translation machinery in vitro, and evaluate the ability of the
ribosome to catalyze their polymerizations. The hydrazine and keto ester moieties are known to react in
solution to form various heterocyclic products. Importantly, the last mechanistic step in heterocyclic formation is
amide bond formation, a specialty of the ribosome. Therefore, I hypothesize that bifunctional monomers
comprised of both these moieties are capable of forming heterocyclic linkages via ribosome mediated
catalysis. Encouraging preliminary results by our collaborative and interdisciplinary research team have
suggested this goal is achievable as we have found the ribosome to be more accommodating than previously
thought. The experiments in this proposal will (1) broaden our understanding of molecular translation, (2)
elucidate the limitations and principles that govern genetic code reprogramming, and (3) expand the synthetic
toolbox for the development of biologically derived SDPs via the ribosome. Accomplishing the aims in this
proposal will increase the backbone diversity currently attainable by the translation machinery and could
produce SDPs that might exhibit greater therapeutic efficacy.
项目概要
重组蛋白生产(RPP)已成为生产拯救生命的有力工具
胰岛素、单克隆抗体和其他关键生物制药等治疗药物。然而,这
有前途的技术受到有效扩展遗传密码以整合的能力的严重限制
用于增强治疗功能的外来单体和主链。目前绝大多数生物聚合物
由翻译机械生产的显示聚酰胺主链;因此,可能的次要和
通过 RPP 合成的蛋白质模拟物可用的三级确认仅限于这些支架。自从
单体序列定义结构,结构定义功能,扩展可用单体池
翻译将产生结构更复杂的生物聚合物,从而增加功能
蛋白质模拟疗法的能力。解决这个问题的一个主要限制是尚未充分探索
核糖体掺入非天然单体的能力,尤其是那些不形成肽的单体
(酰胺)键。为了实现这一目标,该提案旨在开发基因编码的化学物质
由核糖体催化合成结构多样的序列定义聚合物(SDP)
主链(非肽键)。
具体来说,我将设计并合成一个α-肼基酮酯单体库,将它们充电
到正交 tRNA 上,将它们引入体外翻译机器,并评估翻译机器的能力
核糖体催化它们的聚合反应。已知肼和酮酯部分发生反应
溶液生成各种杂环产物。重要的是,杂环形成的最后一步是
酰胺键的形成,是核糖体的一个特点。因此,我假设双功能单体
由这两个部分组成的能够通过核糖体介导形成杂环键
催化。我们的协作和跨学科研究团队取得了令人鼓舞的初步成果
表明这个目标是可以实现的,因为我们发现核糖体比以前更适应
想法。本提案中的实验将(1)拓宽我们对分子翻译的理解,(2)
阐明控制遗传密码重编程的局限性和原则,以及(3)扩展合成
用于通过核糖体开发生物衍生 SDP 的工具箱。实现本次目标
该提案将增加翻译机构目前可实现的骨干多样性,并且可以
产生可能表现出更大治疗效果的 SDP。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ribosome-mediated biosynthesis of pyridazinone oligomers in vitro.
- DOI:10.1038/s41467-022-33701-2
- 发表时间:2022-10-24
- 期刊:
- 影响因子:16.6
- 作者:
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