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Non-Natural Linker Configuration in 2,6-Dipeptidyl-Anthraquinones Enhances the Inhibition of TAR RNA Binding/Annealing Activities by HIV-1 NC and Tat Proteins.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-06-12 , DOI: 10.1021/acs.bioconjchem.8b00104 Alice Sosic 1 , Irene Saccone 2 , Caterina Carraro 1 , Thomas Kenderdine 3 , Elia Gamba 1 , Giuseppe Caliendo 2 , Angela Corvino 2 , Paola Di Vaio 2 , Ferdinando Fiorino 2 , Elisa Magli 2 , Elisa Perissutti 2 , Vincenzo Santagada 2 , Beatrice Severino 2 , Valentina Spada 2 , Dan Fabris 3 , Francesco Frecentese 2 , Barbara Gatto 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-06-12 , DOI: 10.1021/acs.bioconjchem.8b00104 Alice Sosic 1 , Irene Saccone 2 , Caterina Carraro 1 , Thomas Kenderdine 3 , Elia Gamba 1 , Giuseppe Caliendo 2 , Angela Corvino 2 , Paola Di Vaio 2 , Ferdinando Fiorino 2 , Elisa Magli 2 , Elisa Perissutti 2 , Vincenzo Santagada 2 , Beatrice Severino 2 , Valentina Spada 2 , Dan Fabris 3 , Francesco Frecentese 2 , Barbara Gatto 1
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The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of anti-retrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidyl-anthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TAR-binding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins.
中文翻译：
2,6-二肽基-蒽醌中的非天然接头构型增强了HIV-1 NC和Tat蛋白对TAR RNA结合/退火活性的抑制作用。
HIV-1核衣壳（NC）蛋白具有良好的伴侣活性，在病毒生命周期的关键步骤中起着至关重要的作用，因此它代表了抗逆转录病毒药物开发的出色分子靶标。我们一直在寻找能够削弱NC结合/退火活性的候选基因，从而将肽基蒽醌鉴定为一种很有前途的核酸配体。为了阐明抑制决定因素并提高这类化合物的效力，我们现在探索了将平面核与基本侧链连接的连接基的手性效应。我们在这里表明，非天然的接头配置赋予2,6-肽基蒽醌以意想不到的TAR RNA靶向特性，并显着增强了其效能。即使新化合物能够直接与NC蛋白相互作用，它们也表现出对TAR RNA底物的一致更高的亲和力，并且它们的TAR结合特性反映了它们干扰NC-TAR相互作用的能力。基于这些发现，我们提出，具有相同RNA底物但在病毒生命周期的不同阶段起作用的病毒Tat蛋白，构成了此类肽基蒽醌类药物的另一个药物靶向。Tat-TAR相互作用对测试化合物的抑制作用再次与其TAR结合特性相关，而同时未能证明任何直接的Tat结合能力。这些考虑突出了TAR RNA在阐明其抑制机制而非直接蛋白抑制中的重要性。
更新日期：2018-05-23
中文翻译：
2,6-二肽基-蒽醌中的非天然接头构型增强了HIV-1 NC和Tat蛋白对TAR RNA结合/退火活性的抑制作用。
HIV-1核衣壳（NC）蛋白具有良好的伴侣活性，在病毒生命周期的关键步骤中起着至关重要的作用，因此它代表了抗逆转录病毒药物开发的出色分子靶标。我们一直在寻找能够削弱NC结合/退火活性的候选基因，从而将肽基蒽醌鉴定为一种很有前途的核酸配体。为了阐明抑制决定因素并提高这类化合物的效力，我们现在探索了将平面核与基本侧链连接的连接基的手性效应。我们在这里表明，非天然的接头配置赋予2,6-肽基蒽醌以意想不到的TAR RNA靶向特性，并显着增强了其效能。即使新化合物能够直接与NC蛋白相互作用，它们也表现出对TAR RNA底物的一致更高的亲和力，并且它们的TAR结合特性反映了它们干扰NC-TAR相互作用的能力。基于这些发现，我们提出，具有相同RNA底物但在病毒生命周期的不同阶段起作用的病毒Tat蛋白，构成了此类肽基蒽醌类药物的另一个药物靶向。Tat-TAR相互作用对测试化合物的抑制作用再次与其TAR结合特性相关，而同时未能证明任何直接的Tat结合能力。这些考虑突出了TAR RNA在阐明其抑制机制而非直接蛋白抑制中的重要性。
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