Peptide backbone modifications to enhance and study protein folding and binding
肽骨架修饰以增强和研究蛋白质折叠和结合
基本信息
- 批准号:10435444
- 负责人:
- 金额:$ 36.57万
- 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:2021-07-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAmino AcidsBasic ScienceBinding ProteinsBioinformaticsBiological ProductsBiophysicsCarbonChemistryDevelopmentDiagnosisDrug DesignDrug InteractionsEvaluationExperimental DesignsExposure toFutureHydrogen BondingMethodsMissionModificationPeptide SynthesisPeptidesPerceptionPerformancePhasePreventionProceduresProteinsPublic HealthReagentReportingResearchSideSiteSolidStructureSurveysTherapeuticTherapeutic InterventionThioamidesUnited States National Institutes of HealthVertebral columnWorkbasedesigndrug discoveryfunctional grouphuman diseaseinhibitorinnovationknowledge basenovelpreservationprogramsprotein foldingprotein functionracemizationscaffoldsmall moleculestereochemistrytargeted treatmenttool
项目摘要
PROJECT SUMMARY/ABSTRACT
The objective in this application is to exploit stereochemically robust thioamides, at any point in the peptide se-
quence, as biophysical probes to address current barriers in peptide synthesis, folding, and drug discovery.
There is a perception that current methods to incorporate thioamides into peptides are sufficient. However, as
an example, the rapid racemization of the alpha-carbon stereochemistry of thioamide residues during synthesis
belies that perception. Indeed, a survey of reported peptides containing thioamides points to these limitations.
The majority of ‘successful’ sequences incorporate the thioamide close to the N-terminus, where exposure to
synthetic reagents is necessarily minimized during Fmoc solid-phase peptide synthesis (SPPS) procedures.
Thus, the instability of thioamides during Fmoc SPPS present a significant barrier to the synthesis and evalua-
tion of thioamide peptides, and restricts the sequence space in which thioamides can be employed. Anecdotal
reports indicate that many labs have wished to employ thioamides in a variety of peptide studies, but a lack of
documented pitfalls and synthetic options leads to intractable peptide products and, ultimately, abandonment
of such ventures. The approach in this proposal is to protect the thioamide, in analogy to the protection of the
functional groups of amino acid side chains, in order to preserve the thioamide moiety during peptide elonga-
tion. The rationale for this approach is that thioamide protection can be easily included within the standard
SPPS work-flow to enable novel applications in peptide synthesis, backbone modification, and protein-drug
interactions. The research plans of this project will exploit thioamides to probe protein folding and site-selective
insertion other chemistries. Thioamides will be employed in previously uncharted sequence space to address
fundamental questions in protein folding. We will also develop methods to transform thioamides into functional
groups that will unlock new constrained peptide scaffolds. Peptides with persistent structure hold tremendous
promise as therapeutics to bridge the performance gap between small molecules and biologics. Finally, this
work will identify strategies to interrogate and target therapeutically relevant protein-protein interfaces. Interac-
tions between hydrogen bond donors and acceptors of the main-chain of a peptide and a protein binding target
are underutilized in drug design. Based on structural bioinformatics, new strategies to identify underutilized in-
teractions at protein-protein interfaces (PPIs) will assist in the design of more potent inhibitors. Other work will
also develop new tools to interrogate PPIs for which very little structural information may be available to inform
future experimental design. The proposed research is innovative because it represents a substantive departure
from the status quo by developing and employing new methods to preserve thioamide stability, which promises
to unlock new research horizons. The contribution is significant because it is expected to have broad im-
portance in both the study of protein folding and the development of bioactive molecules.
项目总结/摘要
本申请的目的是利用立体化学上稳健的硫代酰胺,在肽序列中的任何点,
序列,作为生物物理探针,以解决目前的障碍,肽合成,折叠和药物发现。
有一种观点认为,目前将硫代酰胺掺入肽中的方法是足够的。但随着
例如,在合成过程中硫代酰胺残基的α-碳立体化学的快速外消旋化
与这种看法不符事实上,对报道的含有硫代酰胺的肽的调查指出了这些限制。
大多数“成功的”序列在接近N-末端处掺入硫代酰胺,其中暴露于硫代酰胺的位置是N-末端。
在Fmoc固相肽合成(SPPS)过程中,合成试剂的使用必须最小化。
因此,在Fmoc SPPS期间硫代酰胺的不稳定性对合成和评价存在显著障碍。
硫代酰胺肽的取代,并限制了可以使用硫代酰胺的序列空间。轶事
报道指出,许多实验室希望在各种肽研究中使用硫代酰胺,但缺乏
记录的缺陷和合成选择导致难以处理的肽产品,并最终被放弃
这样的冒险。该建议中的方法是保护硫代酰胺,类似于保护硫代酰胺。
氨基酸侧链的官能团,以便在肽延长期间保留硫代酰胺部分。
是的。这种方法的基本原理是硫代酰胺保护可以很容易地包括在标准中
SPPS工作流程,使新的应用在肽合成,骨架修饰,和蛋白质药物
交互.本计画的研究计画将利用硫代醯胺来探讨蛋白质折叠与定点分析
插入其他化学物质。硫代酰胺将用于以前未知的序列空间,以解决
蛋白质折叠的基本问题我们还将开发将硫代酰胺转化为功能性酰胺的方法。
将解锁新的受限肽支架。具有持久结构的肽具有巨大的
有望作为治疗剂弥合小分子和生物制剂之间的性能差距。最后
工作将确定询问和靶向治疗相关蛋白质-蛋白质界面的策略。相互作用,
肽主链的氢键供体和受体与蛋白质结合靶之间的连接
在药物设计中没有得到充分利用。基于结构生物信息学,新的战略,以确定未充分利用的-
蛋白质-蛋白质界面(PPI)的相互作用将有助于设计更有效的抑制剂。其他工作将
我还开发了新的工具来询问PPI,这些PPI的结构信息可能很少
未来的实验设计拟议的研究是创新的,因为它代表了一个实质性的出发点。
通过开发和采用新的方法来保持硫代酰胺的稳定性,
开启新的研究视野这一贡献是重要的,因为它预计将有广泛的影响,
在蛋白质折叠的研究和生物活性分子的开发中的重要性。
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)
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Brett VanVeller其他文献
Brett VanVeller的其他文献
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{{ truncateString('Brett VanVeller', 18)}}的其他基金
Peptide backbone modifications to enhance and study protein folding and binding
肽骨架修饰以增强和研究蛋白质折叠和结合
- 批准号:
10275883 - 财政年份:2021
- 资助金额:
$ 36.57万 - 项目类别:
Peptide backbone modifications to enhance and study protein folding and binding
肽骨架修饰以增强和研究蛋白质折叠和结合
- 批准号:
10582205 - 财政年份:2021
- 资助金额:
$ 36.57万 - 项目类别:
Peptide backbone modifications to enhance and study protein folding and binding
肽骨架修饰以增强和研究蛋白质折叠和结合
- 批准号:
10618928 - 财政年份:2021
- 资助金额:
$ 36.57万 - 项目类别:
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