Unveiling RNA‐Binding Properties of Verapamil and Preparation of New Derivatives as Inhibitors of HIV‐1 Tat‐TAR Interaction

Martin Céline; De Piccoli Serena; Gaysinski Marc; Becquart Cécile; Azoulay Stéphane; Di Giorgio Audrey; Duca Maria

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Unveiling RNA‐Binding Properties of Verapamil and Preparation of New Derivatives as Inhibitors of HIV‐1 Tat‐TAR Interaction

机译：揭示维拉帕米的RNA结合性质，并为HIV-1 TAT-TAT相互作用的抑制剂制备新衍生物

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Abstract Targeting RNA using small molecules is now established as a very promising strategy for many therapeutic applications since coding and non‐coding RNAs bear a pivotal role both in viral and bacterial infections as well as in diseases such as cancer. Here, we focused on HIV‐1 TAR RNA as a promising target for the development of new anti‐HIV therapies but also as an ideal model to validate the discovery of original RNA ligands. First, we performed an initial screening of a library of compounds against TAR that led to the discovery of verapamil, a marketed calcium‐channel blocker, as a promising chemical structure for the development of new RNA ligands. The synthesis of a series of analogs of verapamil led to promising structure activity relationships and to the discovery of a conjugate between verapamil and an indole fragment, as an efficient and selective TAR binder able to inhibit Tat/TAR interaction with an IC 50 of 18.8?μM. This work supports the potential of library screening for the discovery of original and selective RNA ligands and illustrates how existing drugs directed against protein targets still need to be studied for RNA binding as a promising strategy in the field of RNA targeting by small molecules.

机译：摘要现在建立使用小分子的靶向RNA作为许多治疗应用的非常有希望的策略，因为编码和非编码RNA在病毒和细菌感染中具有枢转作用以及癌症等疾病。在这里，我们专注于HIV-1焦油RNA作为开发新的抗HIV疗法的有希望的目标，也是验证原始RNA配体的发现的理想模型。首先，我们对焦油进行了初步筛查，该焦油库，导致了亚帕曼，市场钙渠道阻滞剂的发现，作为开发新的RNA配体的有希望的化学结构。一系列维拉帕米类似物的合成导致了有前途的结构活动关系，以及发现维拉帕米和吲哚片段之间的缀合物，作为能够抑制与18.8的IC 50的TAT /焦油相互作用的有效和选择性的焦油粘合剂？ μm。该作品支持图书馆筛查对原始和选择性RNA配体的发现的潜力，并说明了针对蛋白质靶标的现有药物仍然需要研究RNA结合作为由小分子靶向RNA领域的有希望的策略。

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《ChemPlusChem》 |2020年第1期|共10页
作者
Martin Céline; De Piccoli Serena; Gaysinski Marc; Becquart Cécile; Azoulay Stéphane; Di Giorgio Audrey; Duca Maria;
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作者单位

Université C?te d'AzurInstitute of Chemistry of Nice (ICN)28 avenue Valrose 06100 Nice France;

Université C?te d'AzurInstitute of Chemistry of Nice (ICN)28 avenue Valrose 06100 Nice France;

Université C?te d'AzurInstitute of Chemistry of Nice (ICN)28 avenue Valrose 06100 Nice France;

Université C?te d'AzurInstitute of Chemistry of Nice (ICN)28 avenue Valrose 06100 Nice France;

Université C?te d'AzurInstitute of Chemistry of Nice (ICN)28 avenue Valrose 06100 Nice France;

Université C?te d'AzurInstitute of Chemistry of Nice (ICN)28 avenue Valrose 06100 Nice France;

Université C?te d'AzurInstitute of Chemistry of Nice (ICN)28 avenue Valrose 06100 Nice France;

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原文格式 PDF
正文语种 eng
中图分类化学;
关键词
inhibitors; molecular docking; RNA; structure-activity relationships; therapeutics;

机译：抑制剂;分子对接;RNA;结构 - 活动关系;治疗剂;

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专利

1. Unveiling RNA‐Binding Properties of Verapamil and Preparation of New Derivatives as Inhibitors of HIV‐1 Tat‐TAR Interaction [J] . Martin Céline, De Piccoli Serena, Gaysinski Marc, ChemPlusChem . 2020,第1期

机译：揭示维拉帕米的RNA结合性质，并为HIV-1 TAT-TAT相互作用的抑制剂制备新衍生物
2. Tetrahydropyrimidine derivatives inhibit binding of a Tat‐like, arginine‐containing peptide, to HIV TAR RNA in vitro [J] . Ben-Asher Edna, Eisenstein Miriam, Lapidot Aviva FEBS Letters . 1995,第1期

机译：四氢嘧啶衍生物在体外抑制Tat样精氨酸肽与HIV TAR RNA的结合
3. Alpha,alpha-trehalose derivatives bearing guanidino groups as inhibitors to HIV-1 Tat-TAR RNA interaction in human cells. [J] . Wang M, Xu Z, Tu P, Bioorganic and Medicinal Chemistry Letters . 2004,第10期

机译：α，α-海藻糖衍生物携带胍基团作为人体细胞HIV-1 TAT-TAR RNA相互作用的抑制剂。
4. α,α-Trehalose derivatives bearing guanidmo groups as inhibitors to HIV-1 Tat-TAR RNA interaction in human cells [C] . Min Wang, Zhidong Xu, Pengfei Tu, Collection of Academic Papers(2004) . -1

机译：带有胍基的α，α-海藻糖衍生物作为人类细胞中HIV-1 Tat-TAR RNA相互作用的抑制剂
5. Characterization of the HIV-1 TAR RNA-Tat peptide and drug interactions by on-line acoustic wave sensor. [D] . Tassew, Nardos Gobena. 2003

机译：通过在线声波传感器表征HIV-1 TAR RNA-Tat肽和药物相互作用。
6. Multivalent Binding Oligomers Inhibit HIV Tat-TAR Interaction Critical for Viral Replication [O] . Deyun Wang, Jaclyn Iera, Heather Baker, -1

机译：多价结合的低聚物抑制HIV的Tat-TaR相互作用的关键是病毒复制
7. Tetrahydropyrimidine derivatives inhibit binding of a Tat-like, arginine-containing peptide, to HIV TAR RNA in vitro [O] . Lapidot Aviva, Ben-Asher Edna, Eisenstein Miriam 1995

机译：四氢嘧啶衍生物在体外抑制Tat样含精氨酸的肽与HIV TAR RNA的结合

Unveiling RNA‐Binding Properties of Verapamil and Preparation of New Derivatives as Inhibitors of HIV‐1 Tat‐TAR Interaction

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