Geometrically Diverse Lariat Peptide Scaffolds Reveal an Untapped Chemical Space of High Membrane Permeability.
Geometrically Diverse Lariat Peptide Scaffolds Reveal an Untapped Chemical Space of High Membrane Permeability.
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几何多样的肾脏肽支架揭示了高膜渗透性的未开发的化学空间。
DOI：
10.1021/jacs.0c06115
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发表时间：
2021-01-20
影响因子：
15
通讯作者：
Lokey RS
中科院分区：
文献类型：
--
作者：
Kelly CN;Townsend CE;Jain AN;Naylor MR;Pye CR;Schwochert J;Lokey RS
受约束的膜渗透肽提供了参与具有挑战性的细胞内靶点的可能性。结构-渗透性关系已在主链从头到尾环化的环肽中得到广泛研究，如膜渗透性和口服生物可利用的天然产物环孢菌素A。相比之下，从一个末端环化到侧链上的乳酸肽的物理化学性质很少受到关注。许多乳杆菌肽天然产物表现出有趣的生物活性，并且一些，如griselimycin和didemnin B，是膜可渗透的并且具有细胞内靶点。为了研究这些天然产物所例示的化学空间中的结构-渗透性关系，我们使用稳定同位素来编码立体化学生成了支架库，并确定了分子量约为1000的1000多种新型乳肽支架的被动膜渗透性。许多拉里是令人惊讶的渗透性，与许多已知的口服生物可利用的药物相当。被动渗透性强烈依赖于N-甲基化，立体化学和环拓扑结构。观察到各种结构渗透性趋势，包括交替立体化学和高渗透性之间的关系，以及一组高渗透性的共识序列。首次在超过1000种化合物的合成卵磷脂肽中建立了稳健的结构-渗透性关系。
Constrained, membrane-permeable peptides offer the possibility of engaging challenging intracellular targets. Structure-permeability relationships have been extensively studied in cyclic peptides whose backbones are cyclized from head to tail, like the membrane permeable and orally bioavailable natural product cyclosporine A. In contrast, the physicochemical properties of lariat peptides, which are cyclized from one of the termini onto a side chain, have received little attention. Many lariat peptide natural products exhibit interesting biological activities, and some, such as griselimycin and didemnin B, are membrane permeable and have intracellular targets. To investigate the structure-permeability relationships in the chemical space exemplified by these natural products, we generated a library of scaffolds using stable isotopes to encode stereochemistry and determined the passive membrane permeability of over 1000 novel lariat peptide scaffolds with molecular weights around 1000. Many lariats were surprisingly permeable, comparable to many known orally bioavailable drugs. Passive permeability was strongly dependent on N-methylation, stereochemistry, and ring topology. A variety of structure-permeability trends were observed including a relationship between alternating stereochemistry and high permeability, as well as a set of highly permeable consensus sequences. For the first time, robust structure-permeability relationships are established in synthetic lariat peptides exceeding 1000 compounds.
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影响因子：
3.5
作者：
Cleves AE;Jain AN
通讯作者：
Jain AN
使用N-甲基化杂色氨基酸的工程β-折叠。
影响因子：
8.4
作者：
Ghosh D;Lahiri P;Verma H;Mukherjee S;Chatterjee J
通讯作者：
Chatterjee J
影响因子：
4.3
作者：
Fredersdorf, Maic;Kurz, Michael;Thiele, Christina Marie
通讯作者：
Thiele, Christina Marie
影响因子：
1.8
作者：
ANGELL, YM;GARCIAECHEVERRIA, C;RICH, DH
通讯作者：
RICH, DH
影响因子：
7.3
作者：
Marco, E;Martín-Santamaría, S;Gago, F
通讯作者：
Gago, F