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锁定酪氨酸：酪氨酸-DNA磷酸二酯酶I抑制剂瑞西芬A及其类似物的化学合成

Picking the tyrosine-lock: chemical synthesis of the tyrosyl-DNA phosphodiesterase I inhibitor recifin A and analogues.

作者信息

Smallwood Taylor B, Krumpe Lauren R H, Payne Colton D, Klein Victoria G, O'Keefe Barry R, Clark Richard J, Schroeder Christina I, Rosengren K Johan

机构信息

The University of Queensland, School of Biomedical Sciences Brisbane QLD 4072 Australia

Molecular Targets Program, Centre for Cancer Research, National Cancer Institute, National Institute of Health Frederick MD 21702 USA.

出版信息

Chem Sci. 2024 Jun 14;15(33):13227-13233. doi: 10.1039/d4sc01976h. eCollection 2024 Aug 22.

DOI:10.1039/d4sc01976h
PMID:39183914
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11339948/
Abstract

The peptide recifin A is the inaugural member of the structurally intriguing new fold referred to as a tyrosine-lock. Its central four stranded β-sheet is stabilized by a unique arrangement in which three disulfide bonds and their interconnecting backbone form a ring that wraps around one of the strands, resulting in a Tyr side chain being buried in the molecular core. Here we aimed to establish a synthetic route to this complex class of natural products. Full length recifin A was successfully generated through native chemical ligation chemistry joining two 21 amino acid residue fragments. Surprisingly, reduced linear recifin A readily adopts the correct, topologically-complex fold random oxidation of the cysteines, suggesting it is highly energetically favored. Utilizing our synthetic strategy, we generated five recifin A analogues to investigate the structural role of the central Tyr residue and provide the first insights into the structure activity relationship of recifin A towards its cancer target tyrosyl-DNA phosphodiesterase I.

摘要

肽类物质瑞西芬A是被称为酪氨酸锁定的结构引人入胜的新折叠结构的首个成员。其中心的四条链β-折叠通过一种独特的排列得以稳定，在这种排列中，三个二硫键及其相互连接的主链形成一个环绕其中一条链的环，导致一个酪氨酸侧链被埋入分子核心。在此，我们旨在建立一条通往这类复杂天然产物的合成路线。通过天然化学连接化学方法连接两个21个氨基酸残基的片段，成功合成了全长瑞西芬A。令人惊讶的是，还原型线性瑞西芬A在半胱氨酸随机氧化的情况下很容易呈现出正确的、拓扑结构复杂的折叠，这表明其在能量上高度有利。利用我们的合成策略，我们生成了五个瑞西芬A类似物，以研究中心酪氨酸残基的结构作用，并首次深入了解瑞西芬A对其癌症靶点酪氨酰-DNA磷酸二酯酶I的构效关系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/3c97a808102c/d4sc01976h-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/32016fbe0155/d4sc01976h-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/82646c88798a/d4sc01976h-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/4928f18d3ed4/d4sc01976h-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/7fd78a5b616b/d4sc01976h-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/4d1c25e9bca2/d4sc01976h-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/3c97a808102c/d4sc01976h-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/32016fbe0155/d4sc01976h-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/82646c88798a/d4sc01976h-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/4928f18d3ed4/d4sc01976h-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/7fd78a5b616b/d4sc01976h-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/4d1c25e9bca2/d4sc01976h-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/105f/11339948/3c97a808102c/d4sc01976h-f5.jpg

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本文引用的文献

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J Am Chem Soc. 2020 Dec 16;142(50):21178-21188. doi: 10.1021/jacs.0c10418. Epub 2020 Dec 2.
2
Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy.具有发展前景的新型酪氨酰 DNA 磷酸二酯酶 I（Tdp1）抑制剂，将 4-芳基香豆素和单萜类部分结合作为复杂抗肿瘤治疗的组成部分。
Int J Mol Sci. 2019 Dec 23;21(1):126. doi: 10.3390/ijms21010126.
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Three-Dimensional Structure Determination of Peptides Using Solution Nuclear Magnetic Resonance Spectroscopy.
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Dual DNA topoisomerase 1 and tyrosyl-DNA phosphodiesterase 1 inhibition for improved anticancer activity.双重 DNA 拓扑异构酶 1 和酪氨酰-DNA 磷酸二酯酶 1 抑制提高抗癌活性。
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