Cyclic peptide permeability
环肽通透性
基本信息
- 批准号:9895400
- 负责人:
- 金额:$ 9.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-01 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acetic AcidsAffinityAmino AcidsBiochemicalBiologicalBiological AvailabilityBiological ModelsC-terminalCell Membrane PermeabilityCellsChemicalsCollaborationsComplementComputing MethodologiesCyclic PeptidesCyclosporineDNAData SetDiffusionElementsExhibitsFutureHigh Pressure Liquid ChromatographyHydrogen BondingKineticsLeadLibrariesLipid BilayersLiposomesMembraneMethodsModelingMolecular ConformationMolecular WeightN-terminalNatural ProductsNucleic AcidsOralPenetrationPeptidesPermeabilityPharmaceutical PreparationsPhasePhospholipidsPositioning AttributePropertyReportingSchemeSeriesSideSpecificityStructureSystemTechniquesTestingTheoretical modelTherapeuticThermodynamicsVertebral columnWaterbasecomputerized toolsdeep sequencingdesigninsightlipophilicitymolecular dynamicsmolecular sizenovelpassive transportprotein protein interactionscaffoldscreeningsmall moleculesolutestereochemistrytheories
项目摘要
Cyclic peptides can achieve exquisite biochemical potency and specificity against challenging targets such as
protein-protein interactions (PPIs). Although the size and polarity of most cyclic peptides fail to meet Lipinski's
"Rule of 5" for predicting drug-likeness, a growing number of cyclic peptides have been described that exhibit
the ADME properties of small molecule drugs, including high passive cell permeability and oral bioavailability.
These exceptional cases, which include natural products such as cyclosporine A (CSA) as well as a variety of
model systems developed by our group, have generated enthusiasm for the idea that macrocycles may
provide a “middle way” between small molecules and biologics in the pursuit of challenging intracellular targets.
However, achieving drug-like permeability in cyclic peptides is far from straightforward. Simply removing the C-
and N-termini alone is rarely sufficient for achieving therapeutically relevant cell permeability. Other factors
combine to determine the properties of cyclic peptides, and my group has led the effort to elucidate principles
that govern those properties. This proposal aims to 1) identify novel, lariat and stapled peptides that exhibit
high passive membrane permeability; 2) develop selection strategies for filtering DNA-encoded libraries of
cyclic peptides based on the net polarity of the pendant macrocycles; and 3) use NMR and computational
methods to study the detailed mechanisms of permeability across model lipid bilayers. In Aim 1, we will
synthesize mass-encoded libraries based on lariat and stapled peptide designs, and use methods developed in
my group to evaluate their permeabilities en masse. The results will provide insights into structure-permeability
relationships in this chemical space, as well as providing raw materials for the synthesis of libraries aimed at
biochemical target-based screening. In Aim 2, we will begin by synthesizing a series of DNA-tagged cyclic
peptide test systems in which the permeabilities of the pendant macrocycles, which differ only by
stereochemistry at 2 positions, span nearly two log units. We will test a variety of separation schemes, some of
which are known to separate nucleic acids based on the polarity of covalently attached small molecules. We
will then synthesize a diverse library of ~108 lariat peptides and fractionate the library based on the intrinsic
polarity of the attached peptides. Deep sequencing of the pre- and post-selection libraries will illuminate the
“permeability landscape” in cyclic peptides in the 7-mer to 11-mer size range with unprecedented scope and
breadth. In Aim 3, we will use 1H and 19F 2-D NMR techniques, combined with advanced molecular dynamics
simulations performed by our collaborator, Prof. Sereina Riniker (ETH), to study the detailed mechanisms
underlying passive membrane permeability in cyclic peptides. We will synthesize fluorinated derivatives of CSA
and other model systems and study their transport kinetics across synthetic liposomes, and compare
observations with current theoretical models.
环肽可以针对具有挑战性的靶标实现精湛的生化效力和特异性,例如
尽管大多数环肽的大小和极性未能满足 Lipinski 的要求。
用于预测药物相似性的“5 法则”,越来越多的环肽被描述为表现出
小分子药物的 ADME 特性,包括高被动细胞渗透性和口服生物利用度。
这些特殊情况包括环孢素 A (CSA) 等天然产物以及多种
我们小组开发的模型系统,激发了人们对大环化合物可能的想法的热情
在小分子和生物制剂之间提供一条“中间道路”,以追求具有挑战性的细胞内靶标。
然而,在环肽中实现类似药物的渗透性远非简单地去除 C-那么简单。
单独的 N 末端很少足以实现治疗相关的细胞通透性。
结合起来确定环肽的性质,我的小组领导了阐明原理的工作
该提案的目的是 1) 识别表现出新型、套索和钉合的肽。
高被动膜渗透性;2) 制定过滤 DNA 编码文库的选择策略
基于悬垂大环的净极性的环肽;以及 3) 使用 NMR 和计算
在目标 1 中,我们将研究跨模型脂质双层的渗透性详细机制的方法。
合成基于套索和钉合肽设计的质量编码库,并使用开发的方法
我的小组集体评估它们的渗透性,结果将提供对结构渗透性的见解。
该化学空间中的关系,以及为合成库提供原材料,旨在
在目标 2 中,我们将从合成一系列 DNA 标记的环状化合物开始。
肽测试系统,其中悬垂大环化合物的渗透性仅不同
2 个位置的立体化学,跨越近两个对数单位我们将测试各种分离方案,其中一些。
已知它们可以根据共价连接的小分子的极性来分离核酸。
然后将合成约 108 种套索肽的多样化文库,并根据内在特征对文库进行分级
选择前和选择后文库的深度测序将阐明所连接的肽的极性。
7 聚体至 11 聚体尺寸范围内环肽的“渗透性景观”具有前所未有的范围和
在目标 3 中,我们将使用 1H 和 19F 2-D NMR 技术,并结合先进的分子动力学。
由我们的合作者 Sereina Riniker 教授(ETH)进行的模拟,以研究详细的机制
我们将合成 CSA 的氟化衍生物。
和其他模型系统并研究它们在合成脂质体中的运输动力学,并进行比较
与当前理论模型的观察。
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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Robert SCOTT LOKEY其他文献
Robert SCOTT LOKEY的其他文献
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{{ truncateString('Robert SCOTT LOKEY', 18)}}的其他基金
Advancing the basic science of membrane permeability in macrocyclic peptides
推进大环肽膜渗透性的基础科学
- 批准号:
10552484 - 财政年份:2023
- 资助金额:
$ 9.26万 - 项目类别:
Upgrade of core imaging instrumentation and robotics for the UCSC Chemical Screening Center
UCSC 化学筛查中心核心成像仪器和机器人升级
- 批准号:
10177241 - 财政年份:2021
- 资助金额:
$ 9.26万 - 项目类别:
Synthesis and discovery of biologically active cell-permeable cyclic peptides
生物活性细胞渗透性环肽的合成和发现
- 批准号:
8008958 - 财政年份:2010
- 资助金额:
$ 9.26万 - 项目类别:
NCRR: UCSC Integrated Small Molecule Screening Facility
NCRR:UCSC 集成小分子筛选设施
- 批准号:
7221719 - 财政年份:2007
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Small Molecule Modulators of the Actin Cytoskeleton
肌动蛋白细胞骨架的小分子调节剂
- 批准号:
7268781 - 财政年份:2003
- 资助金额:
$ 9.26万 - 项目类别:
Small Molecule Modulators of the Actin Cytoskeleton
肌动蛋白细胞骨架的小分子调节剂
- 批准号:
6707157 - 财政年份:2003
- 资助金额:
$ 9.26万 - 项目类别:
Synthesis and discovery of biologically active cell-permeable cyclic peptides
生物活性细胞渗透性环肽的合成和发现
- 批准号:
7898759 - 财政年份:2003
- 资助金额:
$ 9.26万 - 项目类别:
Small Molecule Modulators of the Actin Cytoskeleton
肌动蛋白细胞骨架的小分子调节剂
- 批准号:
7115942 - 财政年份:2003
- 资助金额:
$ 9.26万 - 项目类别:
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