Conserved coronavirus proteins as targets of broad-spectrum antivirals.
Conserved coronavirus proteins as targets of broad-spectrum antivirals.
复制标题
DOI：
10.1016/j.antiviral.2022.105360
复制
发表时间：
2022-08
影响因子：
7.6
通讯作者：
中科院分区：
文献类型：
--
作者：
冠状病毒是一类单链、阳性的RNA病毒，在过去20年中引起了三次重大疫情：中东呼吸综合征相关冠状病毒(MERS-CoV)、严重急性呼吸综合征冠状病毒(SARS-CoV)和严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。所有疫情都与严重的发病率和死亡率有关。在这项研究中，我们鉴定和探索了关键冠状病毒蛋白中用于开发广谱直接作用的抗冠状病毒化合物的保守结合部位，并用现有的实验数据验证了这种保守对于药物开发的意义。我们已经鉴定了四种具有高度保守的结合位点序列和三维结构相似性的冠状病毒蛋白：PLPro、MPRO、nsp10-nsp16复合体(甲基转移酶)和nsp15核酸内切酶。我们汇编了所有可用的抗病毒药物抑制这些靶点的实验数据，并确定了对多种冠状病毒有活性的化合物。已确定的代表潜在广谱抗病毒药物的化合物包括：GC376，它对6种病毒MPRO有活性(如研究文献所述，在6种测试中)；霉酚酸，它对4种病毒PLPro有活性(4种)；埃美汀，对4种病毒RdRp有活性(4种)。冠状病毒研究中描述的方法结合了对整个病毒家族的序列和结构保守性的评估与可获得的化学结构-抗病毒活性数据的分析，可以探索用于开发针对多个病毒家族的广谱药物。
Coronaviruses are a class of single-stranded, positive-sense RNA viruses that have caused three major outbreaks over the past two decades: Middle East respiratory syndrome–related coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). All outbreaks have been associated with significant morbidity and mortality. In this study, we have identified and explored conserved binding sites in the key coronavirus proteins for the development of broad-spectrum direct acting anti-coronaviral compounds and validated the significance of this conservation for drug discovery with existing experimental data. We have identified four coronaviral proteins with highly conserved binding site sequence and 3D structure similarity: PLpro, Mpro, nsp10-nsp16 complex(methyltransferase), and nsp15 endoribonuclease. We have compiled all available experimental data for known antiviral medications inhibiting these targets and identified compounds active against multiple coronaviruses. The identified compounds representing potential broad-spectrum antivirals include: GC376, which is active against six viral Mpro (out of six tested, as described in research literature); mycophenolic acid, which is active against four viral PLpro (out of four); and emetine, which is active against four viral RdRp (out of four). The approach described in this study for coronaviruses, which combines the assessment of sequence and structure conservation across a viral family with the analysis of accessible chemical structure – antiviral activity data, can be explored for the development of broad-spectrum drugs for multiple viral families.
登录
查看更多内容
影响因子：
5.6
作者：
Cho, Eunice;Rosa, Margarida;Haider, Shozeb
通讯作者：
Haider, Shozeb
影响因子：
7.6
作者：
Brown, Ariane J.;Won, John J.;Sheahan, Timothy P.
通讯作者：
Sheahan, Timothy P.
影响因子：
56.9
作者：
Anand, K;Ziebuhr, J;Hilgenfeld, R
通讯作者：
Hilgenfeld, R
DOI：
10.1016/j.dsx.2020.04.020
发表时间：
2020-07-01
影响因子：
10
作者：
Astuti, Indwiani;Ysrafil
通讯作者：
Ysrafil
影响因子：
5.4
作者：
Aouadi, Wahiba;Blanjoie, Alexandre;Decroly, Etienne
通讯作者：
Decroly, Etienne