Potent Dual Polymerase/Exonuclease Inhibitory Activities of Antioxidant Aminothiadiazoles Against the COVID-19 Omicron Virus: A Promising In Silico/In Vitro Repositioning Research Study.
Potent Dual Polymerase/Exonuclease Inhibitory Activities of Antioxidant Aminothiadiazoles Against the COVID-19 Omicron Virus: A Promising In Silico/In Vitro Repositioning Research Study.
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DOI：
10.1007/s12033-022-00551-8
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发表时间：
2024-04
影响因子：
2.6
通讯作者：
Eltayb, Wafa A.
中科院分区：
文献类型：
--
作者：
Rabie, Amgad M.;Eltayb, Wafa A.
关键词：
近日，天然和合成含氮杂环抗病毒药物成为治疗严重急性呼吸综合征冠状病毒2型感染及其伴发疾病--冠状病毒病2019(新冠肺炎)的首选药物。与此同时，一种新的SARS-CoV-2毒株--欧米克龙变种及其亚型的神秘进化，在持续不断的新冠肺炎之战中引发了一场新的对抗。由于RdRp和外显子在所有SARS-CoV-2毒株中广泛保守，因此用同一配体同时打击SARS-CoV-2的两个主要增殖酶依赖RNA聚合酶(RdRp)和3‘-to-5’外显子(Exon)是一种高效的双重途径，可以阻止SARS-CoV-2的复制和阻止新冠肺炎的进展。在这里，目前的计算/生物学研究筛选了我们以前的含氮杂环化合物的小库，寻找最理想的候选药物，可以预测通过这种双重方法能够有效地发挥作用。理论筛选得到了三种有希望的1，3，4-噻二唑型抗氧剂含氮杂环化合物，它们是CoViTris2022、Taroxaz-26和ChloViD2022。进一步的实验评估首次证明，利用体外抗RdRp/外显子和抗SARS-CoV-2生物测定，ChloViD2022、CoViTris2022和Taroxaz-26能有效抑制新强毒株的复制，体外极微小的抗RdRp和抗SARS-CoV-2EC50值分别为0.17和0.41μM，0.21和0.69μM，超过抗新冠肺炎药物Taroxaz-26和0.23和0.73μM。电子计算的初步结果很大程度上支持了这些生化结果，表明这三个分子有力地攻击了SARS-CoV-2(Omicron变体)RdRp的关键催化区域和外显子的关键活性部位。此外，CoViTris2022、Taroxaz-26和ChloViD2022分子的理想化药理特征使它们相对来说是典型的SARS-CoV-2复制和校对的双重作用抑制剂，其高度灵活的结构为各种化学衍生化打开了大门。简而言之，这项综合性工作的目前关键发现揭示了三种2-氨基噻二唑：CoViTris2022、Taroxaz-26和ChloViD2022很有希望的重新定位潜力，从而成功干扰冠状病毒2聚合酶/外切核酸酶与四个主要核苷酸的关键生物相互作用，从而治愈新冠肺炎感染，鼓励我们迅速启动这三种药物广泛的临床前/临床抗新冠肺炎评估。通过核苷模拟抑制SARS-CoV-2聚合酶和外显子的双重作用是治疗新冠肺炎感染的一种非常有效的新方法。目前，羟基含氮杂环化合物被认为是新冠肺炎治疗的首选药物。大量的计算研究揭示了三个合成的5-取代-2-氨基-1，3，4-噻二唑，CoViTris2022，Taroxaz-26和ChloViD2022，具有理想的抗RdRp/外显子特性。ChloViD2022的生化抗RdRp EC50值为0.17，而μM.ChloViD2022的EC50值为0.41%，μM的EC50值为0.41.网上版载有补充材料，可在10.1007/s12033-022-00551-8查阅。
Recently, natural and synthetic nitrogenous heterocyclic antivirals topped the scene as first choices for the treatment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their accompanying disease, the coronavirus disease 2019 (COVID-19). Meanwhile, the mysterious evolution of a new strain of SARS-CoV-2, the Omicron variant and its sublineages, caused a new defiance in the continual COVID-19 battle. Hitting the two principal coronaviral-2 multiplication enzymes RNA-dependent RNA polymerase (RdRp) and 3′-to-5′ exoribonuclease (ExoN) synchronously using the same ligand is a highly effective novel dual pathway to hinder SARS-CoV-2 reproduction and stop COVID-19 progression irrespective of the SARS-CoV-2 variant type since RdRps and ExoNs are widely conserved among all SARS-CoV-2 strains. Herein, the present computational/biological study screened our previous small libraries of nitrogenous heterocyclic compounds, searching for the most ideal drug candidates predictably able to efficiently act through this double approach. Theoretical filtration gave rise to three promising antioxidant nitrogenous heterocyclic compounds of the 1,3,4-thiadiazole type, which are CoViTris2022, Taroxaz-26, and ChloViD2022. Further experimental evaluation proved for the first time, utilizing the in vitro anti-RdRp/ExoN and anti-SARS-CoV-2 bioassays, that ChloViD2022, CoViTris2022, and Taroxaz-26 could effectively inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC50 values of 0.17 and 0.41 μM for ChloViD2022, 0.21 and 0.69 μM for CoViTris2022, and 0.23 and 0.73 μM for Taroxaz-26, respectively, transcending the anti-COVID-19 drug molnupiravir. The preliminary in silico outcomes greatly supported these biochemical results, proposing that the three molecules potently strike the key catalytic pockets of the SARS-CoV-2 (Omicron variant) RdRp’s and ExoN’s vital active sites. Moreover, the idealistic pharmacophoric hallmarks of CoViTris2022, Taroxaz-26, and ChloViD2022 molecules relatively make them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading, with their highly flexible structures open for various kinds of chemical derivatization. To cut it short, the present pivotal findings of this comprehensive work disclosed the promising repositioning potentials of the three 2-aminothiadiazoles, CoViTris2022, Taroxaz-26, and ChloViD2022, to successfully interfere with the crucial biological interactions of the coronaviral-2 polymerase/exoribonuclease with the four principal RNA nucleotides, and, as a result, cure COVID-19 infection, encouraging us to rapidly start the three drugs’ broad preclinical/clinical anti-COVID-19 evaluations. Dual SARS-CoV-2 polymerase (RdRp) and exoribonuclease (ExoN) inhibition via nucleoside mimicry is a very effective novel approach for COVID-19 infection therapy. Hydroxylated nitrogenous heterocyclic compounds are currently considered first choices in COVID-19 therapy. Extensive computational investigations disclosed three synthetic 5-substituted-2-amino-1,3,4-thiadiazoles, CoViTris2022, Taroxaz-26, and ChloViD2022, with ideal anti-RdRp/ExoN features. ChloViD2022 was ranked the top among the three NAs, with biochemical anti-RdRp EC50 value of 0.17 μM. ChloViD2022 accordingly displayed excellent anti-SARS-CoV-2 EC50 value of 0.41 μM against the Omicron variant. The online version contains supplementary material available at 10.1007/s12033-022-00551-8.
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影响因子：
4.4
作者：
Chien M;Anderson TK;Jockusch S;Tao C;Li X;Kumar S;Russo JJ;Kirchdoerfer RN;Ju J
通讯作者：
Ju J
影响因子：
3.7
作者：
Ip A;Ahn J;Zhou Y;Goy AH;Hansen E;Pecora AL;Sinclaire BA;Bednarz U;Marafelias M;Sawczuk IS;Underwood JP 3rd;Walker DM;Prasad R;Sweeney RL;Ponce MG;La Capra S;Cunningham FJ;Calise AG;Pulver BL;Ruocco D;Mojares GE;Eagan MP;Ziontz KL;Mastrokyriakos P;Goldberg SL
通讯作者：
Goldberg SL
影响因子：
4.1
作者：
Rabie AM
通讯作者：
Rabie AM
影响因子：
3.8
作者：
Rabie AM
通讯作者：
Rabie AM
DOI：
10.1073/pnas.2106379119
发表时间：
2022-03-01
影响因子：
11.1
作者：
Moeller NH;Shi K;Demir Ö;Belica C;Banerjee S;Yin L;Durfee C;Amaro RE;Aihara H
通讯作者：
Aihara H