Analysis of Structure–Activity Relationships Based on the Hepatitis?C Virus SLIIb Internal Ribosomal Entry Sequence RNA‐Targeting GGHYRFK?Cu Complex

Ross Martin James; Fidai Insiya; Cowan James A.

摘要

Abstract > New therapeutics for targeting the hepatitis?C virus (HCV) have been released in recent years. Although they are less prone to resistance, they are still administered in cocktails as a combination of drugs targeting various aspects of the viral life cycle. Herein, we aim to contribute to an arsenal of new HCV therapeutics by targeting the HCV internal ribosomal entry sequence (IRES) RNA through the development of catalytic metallodrugs that function to degrade rather than inhibit the target molecule. Based on a previously characterized HCV IRES stem‐loop IIb RNA‐targeting metallopeptide Cu‐GGHYrFK ( 1? Cu), an all‐ <sc>l</sc> analogue ( 3? Cu) and a series of additional complexes with single alanine substitutions in the targeting domain were prepared and screened to determine the influence each amino acid side chain on RNA localization and recognition, and catalytic reactivity toward the RNA. Additional substitutions of the tyrosine position in complex 3? Cu were also investigated. Good agreement between calculated and measured binding affinities provided support for in silico modeling of the SLIIb RNA binding site and correlations with RNA cleavage sites. Examination of the cleavage products from reaction of the Cu complexes with SLIIb provided mechanistic insights, with the first observation of the 5′‐geminal diol and 5′‐phosphopropenal as products through the use of a Cu ? ATCUN catalytic motif. Together, the data yielded insights into structure–function relationships that will guide future optimization efforts. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract Type =“Main”XML：Lang =“en”> <标题类型=“main”>摘要</ title> >用于靶向肝炎的新治疗方法，近年来已发布病毒（HCV）。虽然它们易于耐受性，但它们仍然以鸡尾酒施用，作为靶向病毒生命周期的各个方面的药物的组合。在此，我们的目的是通过靶向HCV内部核糖体进入序列（IRES）RNA通过发挥作用而不是抑制靶分子的催化金属化物质来促进新HCV治疗剂的阿森纳。基于先前表征的HCV IRES茎环IIB RNA靶向金属肽Cu-GGHγRFK（<B> 1→β-Cu），全 - <sc> L </ sc>类似物（ 3？< / B> Cu）和一系列具有靶向结构域中的丙氨酸取代的另外的络合物并筛选，以确定每个氨基酸侧链对RNA定位和识别的影响，以及对RNA的催化反应性。还研究了络合物中酪氨酸位置的附加取代。计算和测量的结合亲和力之间的良好一致性为SLIIB RNA结合位点的硅模型提供了支持，以及与RNA切割位点的相关性。从Cu复合物与SLIIB的反应检查裂解产物，通过使用Cu <B> Atcun，首先观察5'-初始二醇和5'-磷普洛替氏素作为产物。</ B> Atcun催化基序。在一起，数据产生了洞察的结构功能关系，这些关系将引导未来的优化努力。 </ p> </ abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" > 著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-16039/'>《Chembiochem: A European journal of chemical biology 》</a> <b style="margin: 0 2px;">|</b><span>2017年第17期</span><b style="margin: 0 2px;">|</b> <span>共12页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Ross Martin James&option=202" target="_blank" rel="nofollow">Ross Martin James;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Fidai Insiya&option=202" target="_blank" rel="nofollow">Fidai Insiya;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Cowan James A.&option=202" target="_blank" rel="nofollow">Cowan James A.;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Evans Laboratory of ChemistryThe Ohio State University100 West 18th Avenue Columbus OH 43210 USA;</p> <p>Evans Laboratory of ChemistryThe Ohio State University100 West 18th Avenue Columbus OH 43210 USA;</p> <p>Evans Laboratory of ChemistryThe Ohio State University100 West 18th Avenue Columbus OH 43210 USA;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li> <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span> <a href="https://www.zhangqiaokeyan.com/clc/179.html" title="分子生物学">分子生物学 ;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=ATCUN motif&option=203" rel="nofollow">ATCUN motif;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=copper&option=203" rel="nofollow">copper;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=hepatitis?C virus&option=203" rel="nofollow">hepatitis?C virus;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=metalloproteins&option=203" rel="nofollow">metalloproteins;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=RNA cleavage&option=203" rel="nofollow">RNA cleavage;</a> </p> <div class="translation"> 机译：Atcun主题;铜;肝炎？C病毒;金属蛋白;RNA裂解; </div> </li> </ul> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab clearfix"> <ul> <li class="active" >外文文献</li> <li >中文文献</li> <li >专利</li> </ul> </div> <div class="similarity_details"> <ul > <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/journal-foreign-detail/0704022055497.html">Analysis of Structure–Activity Relationships Based on the Hepatitis?C Virus SLIIb Internal Ribosomal Entry Sequence RNA‐Targeting GGHYRFK?Cu Complex</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Ross Martin James&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Ross Martin James,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Fidai Insiya&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Fidai Insiya,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Cowan James A.&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Cowan James A. </a> <a href="/journal-foreign-16039/" target="_blank" rel="nofollow" class="tuijian_authcolor">Chembiochem: A European journal of chemical biology .</a> <span>2017</span> <span>,第17期</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：基于肝炎的结构 - 活性关系分析，C病毒SLIIB内部核糖体进入序列RNA靶向GGHyrFK？Cu复合物</span> </p> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/journal-foreign-detail/0704012481338.html">GENETIC ANALYSIS OF INTERNAL RIBOSOMAL ENTRY SITE ON HEPATITIS C VIRUS RNA - IMPLICATION FOR INVOLVEMENT OF THE HIGHLY ORDERED STRUCTURE AND CELL TYPE-SPECIFIC TRANSACTING FACTORS</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Nobuhiko Kamoshita&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Nobuhiko Kamoshita,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Kyoko Tsukiyama-Kohara&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Kyoko Tsukiyama-Kohara,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Michinori Kohara&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Michinori Kohara,</a> <a href="/journal-foreign-32078/" target="_blank" rel="nofollow" class="tuijian_authcolor">Virology .</a> <span>1997</span> <span>,第1期</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：丙型肝炎病毒RNA内部核糖体进入位点的遗传分析-涉及高度有序的结构和细胞类型特异性交易因子</span> </p> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/academic-journal-foreign_proceedings-national-academy-sciences-united-states-america_thesis/020417237869.html">Activity of a type 1 picornavirus internal ribosomal entry site is determined by sequences within the 3' nontranslated region</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Elena Dobrikova&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Elena Dobrikova,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Paola Florez&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Paola Florez,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Shelton Bradrick&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Shelton Bradrick,</a> <a href="/journal-foreign-6544/" target="_blank" rel="nofollow" class="tuijian_authcolor">Proceedings of the National Academy of Sciences of the United States of America .</a> <span>2003</span> <span>,第25期</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：1型小核糖核酸病毒内部核糖体进入位点的活性由3'非翻译区内的序列决定</span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/academic-conference-foreign_meeting-255460_thesis/0705014985632.html">Identification of a cellular protein required for hepatitis C virus internal ribosome entry site (IRES)-mediated translation</a> <b>[C]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=T. 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href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=马文囡&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,马文囡</a> <span> <a href="/journal-cn-9408/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 食品与生物技术学报 </a> </span> <span> . 2019</span><span> ,第007期</span> </span> </div> </li> <li> <div> <b>6. </b><a class="enjiyixqcontent" href="/academic-conference-cn_meeting-15372_thesis/020221388825.html">茶尺蠖小RNA病毒RNA依赖的RNA聚合酶及内部核糖体进入位点元件研究</a> <b>[C]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=林美娟&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 林美娟</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=卢杰&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,卢杰</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=叶珊&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,叶珊</a> <span> <a href="/conference-cn-15372/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 第八届全国病毒学学术研讨会 </a> <span> <span> . 2009</span> </span> </div> </li> <li> <div> <b>7. </b><a class="enjiyixqcontent" href="/academic-degree-domestic_mphd_thesis/020314103457.html">丙型肝炎病毒内部核糖体进入位点的三级结构研究</a> <b>[A] </b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=宁俊红&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 宁俊红</a> <span> . 2008</span> </span> </div> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/patent-detail/06120112009517.html">一种基于全长小亚基核糖体RNA的反转录来分析微生物群落结构的方法</a> <b>[P]</b> . <span> 中国专利： CN111996245A </span> <span> . 2020-11-27</span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/patent-detail/06120100474724.html">一种基于字符切片技术的含PAM结构gRNA靶向序列筛选方法及应用</a> <b>[P]</b> . <span> 中国专利： CN109411022A </span> <span> . 2019-03-01</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130439242987.html">Trans-Splicing Ribozyme Mediated Selective Induction of Gene Activity in Hepatitis C Virus Internal Ribosome Entry Site-Expressing Cells</a> <b>[P]</b> . <span> 外国专利：  KR100490699B1 </span> <span> . 2005-05-19</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：反式核酶介导的丙型肝炎病毒内部核糖体进入位点表达细胞中基因活性的选择性诱导。 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130441654295.html">- Trans-Splicing Ribozyme Mediated Selective Induction of Gene Activity in Hepatitis C Virus Internal Ribosome Entry Site-Expressing Cells</a> <b>[P]</b> . <span> 外国专利：  KR20040031405A </span> <span> . 2004-04-13</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：-跨接核酶介导的丙型肝炎病毒内部核糖体进入位点表达细胞基因活性的选择性诱导 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130427469525.html">SMALL RNA INTERFERENCE TARGET SITE SEQUENCES OF HEPATITIS B VIRUS AND SMALL INTERFERENCE RNAS AND THE COMPOSITIONS AND USES THEREOF</a> <b>[P]</b> . <span> 外国专利：  WO2010012244A1 </span> <span> . 2010-02-04</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：乙型肝炎病毒和小干扰RNA的小RNA干扰靶位点序列及其组成和用途 </span> </p> </li> </ul> </div> </div> </div> <div class="theme cardcommon" style="overflow: auto;display:none"> <h3 class="all_title" id="enpatent55">相关主题</h3> <ul id="subject"> </ul> </div> </div> </div> </div> <div class="right rightcon"> <div class="details_img cardcommon clearfix" style="margin-bottom: 10px;display:none;" > </div> </div> </div> <div id="thesis_get_original1" class="downloadBth" style="bottom: 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