Matos Aline da Rocha, Caetano Braulia Costa, de Almeida Filho João Luiz, Martins Jéssica Santa Cruz de Carvalho, de Oliveira Michele Gabrielle Pacheco, Sousa Thiago das Chagas, Horta Marco Aurélio Pereira, Siqueira Marilda Mendonça, Fernandez Jorge Hernandez
Laboratório de Virus Respiratórios e do Sarampo, Insituto Oswaldo Cruz, Fundação Oswaldo Cruz (LVRS-IOC-Fiocruz), Rio de Janeiro, Brazil.
Laboratório de Química e Função de Proteínas e Peptídeos, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense (LQFPP-CBB-UENF), Campos dos Goytacazes, Brazil.
Front Microbiol. 2022 Feb 10;13:828984. doi: 10.3389/fmicb.2022.828984. eCollection 2022.
The COVID-19 pandemic has had an unprecedented impact on the global economy and public health. Its etiologic agent, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible, pathogenic and has a rapid global spread. Currently, the increase in the number of new confirmed cases has been slowed down due to the increase of vaccination in some regions of the world. Still, the rise of new variants has influenced the detection of additional waves of rising cases that some countries have experienced. Since the virus replication cycle is composed of many distinct stages, some viral proteins related to them, as the main-protease (Mpro) and RNA dependent RNA polymerase (RdRp), constitute individual potential antiviral targets. In this study, we challenged the mentioned enzymes against compounds pre-approved by health regulatory agencies in a virtual screening and later in Molecular Mechanics/Poisson-Bolzmann Surface Area (MM/PBSA) analysis. Our results showed that, among the identified potential drugs with anti-SARS-CoV-2 properties, Hypericin, an important component of the that presents antiviral and antitumoral properties, binds with high affinity to viral Mpro and RdRp. Furthermore, we evaluated the activity of Hypericin anti-SARS-CoV-2 replication in an model of Vero-E6 infected cells. Therefore, we show that Hypericin inhibited viral replication in a dose dependent manner. Moreover, the cytotoxicity of the compound, in cultured cells, was evaluated, but no significant activity was found. Thus, the results observed in this study indicate that Hypericin is an excellent candidate for repurposing for the treatment of COVID-19, with possible inhibition of two important phases of virus maturation.
新冠疫情对全球经济和公共卫生产生了前所未有的影响。其病原体严重急性呼吸综合征冠状病毒2（SARS-CoV-2）具有高度传染性、致病性，且在全球迅速传播。目前，由于世界某些地区疫苗接种的增加，新增确诊病例数的增长已放缓。然而，新变种的出现影响了一些国家所经历的新增病例数上升的检测。由于病毒复制周期由许多不同阶段组成，一些与之相关的病毒蛋白，如主要蛋白酶（Mpro）和RNA依赖性RNA聚合酶（RdRp），构成了各自潜在的抗病毒靶点。在本研究中，我们在虚拟筛选以及随后的分子力学/泊松-玻尔兹曼表面积（MM/PBSA）分析中，用卫生监管机构预先批准的化合物对上述酶进行了测试。我们的结果表明，在已鉴定的具有抗SARS-CoV-2特性的潜在药物中，金丝桃素是贯叶连翘的一种重要成分，具有抗病毒和抗肿瘤特性，它与病毒Mpro和RdRp具有高亲和力结合。此外，我们在Vero-E6感染细胞模型中评估了金丝桃素抗SARS-CoV-2复制的活性。因此，我们表明金丝桃素以剂量依赖性方式抑制病毒复制。此外，还评估了该化合物在培养细胞中的细胞毒性，但未发现明显活性。因此，本研究中观察到的结果表明，金丝桃素是重新用于治疗COVID-19的极佳候选药物，可能会抑制病毒成熟的两个重要阶段。
