Rabie Amgad M, Abdalla Mohnad
Dr. Amgad Rabie's Research Lab. for Drug Discovery (DARLD) 35511 Mansoura Dakahlia Governorate Egypt.
Head of Drug Discovery & Clinical Research Department Dikernis General Hospital (DGH) Magliss El-Madina Street Dikernis 35744 Dikernis Dakahlia Governorate Egypt.
ChemistrySelect. 2022 Dec 13;7(46):e202201912. doi: 10.1002/slct.202201912. Epub 2022 Dec 8.
Given the rapid progression of the coronavirus disease 2019 (COVID-19) pandemic, an ultrafast response was urgently required to handle this major public crisis. To contain the pandemic, investments are required to develop diagnostic tests, prophylactic vaccines, and novel therapies. Lately, nucleoside analog (NA) antivirals topped the scene as top options for the treatment of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Meanwhile, the continuous generation of new lineages of the SARS-CoV-2 Omicron variant caused a new challenge in the persistent COVID-19 battle. Hitting the two crucial SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) collectively together using only one single ligand is a very successful new approach to stop SARS-CoV-2 multiplication and combat COVID-19 irrespective of the SARS-CoV-2 variant type because RdRps and ExoNs are broadly conserved among all SARS-CoV-2 strains. Herein, the current comprehensive study investigated most NAs libraries, searching for the most ideal drug candidates expectedly able to perfectly act through this double tactic. Gradual computational filtration gave rise to six different promising NAs, which are riboprine, forodesine, tecadenoson, nelarabine, vidarabine, and maribavir, respectively. Further biological assessment proved for the first time, using the anti-RdRp/ExoN and anti-SARS-CoV-2 bioassays, that riboprine and forodesine, among all the six tested NAs, are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute anti-RdRp and anti-SARS-CoV-2 EC values of about 0.22 and 0.49 μM for riboprine and about 0.25 and 0.73 μM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. The prior data supported these biochemical findings, suggesting that riboprine and forodesine molecules strongly hit the key catalytic pockets of the SARS-CoV-2 (Omicron variant) RdRp's and ExoN's main active sites. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading, with their relatively flexible structures open for diverse types of chemical derivatization. In Brief, the current important results of this comprehensive study revealed the interesting repurposing potentials of, mainly, the two nucleosides riboprine and forodesine to effectively shut down the polymerase/exoribonuclease-RNA nucleotides interactions of the SARS-CoV-2 Omicron variant and consequently treat COVID-19 infections, motivating us to rapidly begin the two drugs' broad preclinical/clinical anti-COVID-19 bioevaluations, hoping to combine both drugs soon in the COVID-19 treatment protocols.
鉴于2019年冠状病毒病（COVID-19）大流行的迅速发展，迫切需要做出超快反应来应对这一重大公共危机。为了控制疫情，需要投资开发诊断测试、预防性疫苗和新型疗法。最近，核苷类似物（NA）抗病毒药物成为治疗由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染引起的COVID-19的首选。与此同时，SARS-CoV-2奥密克戎变种新谱系的不断出现给持续的COVID-19抗疫斗争带来了新挑战。仅使用一种单一配体共同作用于两种关键的SARS-CoV-2酶——RNA依赖性RNA聚合酶（RdRp）和3'至5'外切核糖核酸酶（ExoN），是一种非常成功的新方法，可阻止SARS-CoV-2增殖并对抗COVID-19，无论SARS-CoV-2变种类型如何，因为RdRp和ExoN在所有SARS-CoV-2毒株中广泛保守。在此，当前的综合研究调查了大多数NA文库，以期寻找有望通过这种双重策略完美发挥作用的最理想候选药物。逐步的计算筛选产生了六种不同的有前景的NA，分别是利巴嘌呤、福多司坦、替卡地松、奈拉滨、阿糖腺苷和马立巴韦。进一步的生物学评估首次使用抗RdRp/ExoN和抗SARS-CoV-2生物测定法证明，在所有六种测试的NA中，利巴嘌呤和福多司坦能够有力地抑制SARS-CoV-2新毒株的复制，利巴嘌呤的抗RdRp和抗SARS-CoV-2的半数有效浓度（EC）值极低，分别约为0.22和0.49 μM，福多司坦的分别约为0.25和0.73 μM，超过了瑞德西韦和新型抗COVID-19药物莫努匹拉韦。先前的数据支持了这些生化研究结果，表明利巴嘌呤和福多司坦分子强烈作用于SARS-CoV-2（奥密克戎变种）RdRp和ExoN主要活性位点的关键催化口袋。此外，利巴嘌呤和福多司坦分子理想的药效团特征使其成为SARS-CoV-2复制和校对的典型双作用抑制剂，其相对灵活的结构便于进行多种类型的化学衍生化。简而言之，这项综合研究的当前重要结果揭示了主要是利巴嘌呤和福多司坦这两种核苷具有有趣的重新利用潜力，可有效阻断SARS-CoV-2奥密克戎变种的聚合酶/外切核糖核酸酶-RNA核苷酸相互作用，从而治疗COVID-19感染，促使我们迅速开始这两种药物广泛的临床前/临床抗COVID-19生物评估，希望很快能将这两种药物联合用于COVID-19治疗方案中。
