Abstract:
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated coronavirus disease 2019 (COVID-19) infection remains a global pandemic and health emergency with overwhelming social and economic impacts throughout the world. Therapeutics for COVID-19 are limited to only remdesivir; therefore, there is a need for combined, multidisciplinary efforts to develop new therapeutic molecules and explore the effectiveness of existing drugs against SARS-CoV-2. In the present study, we reported eight (SCOV-L-02, SCOV-L-09, SCOV-L-10, SCOV-L-11, SCOV-L-15, SCOV-L-18, SCOV-L-22, and SCOV-L-23) novel structurally related small-molecule derivatives of niclosamide (SCOV-L series) for their targeting potential against angiotensin-converting enzyme-2 (ACE2), type II transmembrane serine protease (TMPRSS2), and SARS-COV-2 nonstructural proteins (NSPs) including NSP5 (3CLpro), NSP3 (PLpro), and RdRp. Our correlation analysis suggested that ACE2 and TMPRSS2 modulate host immune response via regulation of immune-infiltrating cells at the site of tissue/organs entries. In addition, we identified some TMPRSS2 and ACE2 microRNAs target regulatory networks in SARS-CoV-2 infection and thus open up a new window for microRNAs-based therapy for the treatment of SARS-CoV-2 infection. Our in vitro study revealed that with the exception of SCOV-L-11 and SCOV-L-23 which were non-active, the SCOV-L series exhibited strict antiproliferative activities and non-cytotoxic effects against ACE2- and TMPRSS2-expressing cells. Our molecular docking for the analysis of receptor-ligand interactions revealed that SCOV-L series demonstrated high ligand binding efficacies (at higher levels than clinical drugs) against the ACE2, TMPRSS2, and SARS-COV-2 NSPs. SCOV-L-18, SCOV-L-15, and SCOV-L-09 were particularly found to exhibit strong binding affinities with three key SARS-CoV-2\'s proteins: 3CLpro, PLpro, and RdRp. These compounds bind to the several catalytic residues of the proteins, and satisfied the criteria of drug-like candidates, having good adsorption, distribution, metabolism, excretion, and toxicity (ADMET) pharmacokinetic profile. Altogether, the present study suggests the therapeutic potential of SCOV-L series for preventing and managing SARs-COV-2 infection and are currently under detailed investigation in our lab.
摘要:
严重急性呼吸道综合症冠状病毒-2(SARS-CoV-2)介导的2019年冠状病毒病(COVID-19)感染仍然是全球大流行和卫生紧急情况,对全世界产生了巨大的社会和经济影响。COVID-19的治疗学仅限于雷米西韦;因此,需要结合,多学科努力开发新的治疗分子和探索现有药物对抗SARS-CoV-2的有效性。在本研究中,我们报道了八种(SCOV-L-02,SCOV-L-09,SCOV-L-10,SCOV-L-11,SCOV-L-15,SCOV-L-18,SCOV-L-22和SCOV-L-23)新型结构相关的氯硝柳胺小分子衍生物(SCOV-L系列)II型跨膜丝氨酸蛋白酶(TMPRSS2),和SARS-COV-2非结构蛋白(NSP),包括NSP5(3CLpro),NSP3(PLpro),和RdRp。我们的相关性分析表明,ACE2和TMPRSS2通过调节组织/器官进入部位的免疫浸润细胞来调节宿主的免疫反应。此外,我们在SARS-CoV-2感染中鉴定了一些TMPRSS2和ACE2microRNAs靶向调控网络,从而为基于microRNAs的SARS-CoV-2感染治疗开辟了一个新的窗口.我们的体外研究表明,除了无活性的SCOV-L-11和SCOV-L-23,SCOV-L系列对表达ACE2-和TMPRSS2的细胞表现出严格的抗增殖活性和非细胞毒性作用。我们用于分析受体-配体相互作用的分子对接表明,SCOV-L系列对ACE2,TMPRSS2和SARS-COV-2NSP具有较高的配体结合功效(比临床药物高)。特别发现SCOV-L-18,SCOV-L-15和SCOV-L-09与三种关键的SARS-CoV-2蛋白:3CLpro,PLpro,和RdRp。这些化合物与蛋白质的几个催化残基结合,并满足类似药物的候选标准,具有良好的吸附性,分布,新陈代谢,排泄,和毒性(ADMET)药代动力学概况。总之,本研究提示SCOV-L系列在预防和管理SARs-COV-2感染方面的治疗潜力,目前我们实验室正在进行详细研究.