Department of Physics, Florida International University, 11200 SW 8th St, Miami, FL 33199, USA.
Biomolecular Sciences Institute, Florida International University, 11200 SW 8th St, Miami, FL 33199, USA.
J Med Microbiol. 2020 Jun;69(6):864-873. doi: 10.1099/jmm.0.001203. Epub 2020 May 29.
The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics. To identify drugs against COVID-19, we performed an virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the virtual screen. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our findings.
SARS-CoV-2 的出现让人类措手不及。继 2002 年 SARS-CoV 爆发和 10 年后 MERS-CoV 爆发之后，SARS-CoV-2 是不到 20 年内第三种跨越物种屏障并开始通过人际传播的冠状病毒。它是三种中最具传染性的，目前导致 COVID-19 大流行。目前还没有批准用于 COVID-19 的治疗方法。我们之前提出了可以作为多种冠状病毒抗病毒药物结合位点的靶标，在这里，我们着手寻找可以重新用于 COVID-19 治疗的现有药物。为了确定针对 COVID-19 的药物，我们使用美国食品和药物管理局（FDA）批准的针对 RNA 依赖性 RNA 聚合酶（RdRP）的药物进行了虚拟筛选，RdRP 是冠状病毒复制的关键酶。最初，没有 SARS-CoV-2 的 RdRP 结构。我们进行了基本的序列和结构分析，以确定 SARS-CoV 的 RdRP 是否是合适的替代品。我们进行了分子动力学模拟，生成了多个起始构象，用于虚拟筛选。在此期间，获得了 SARS-CoV-2 的 RdRP 结构，并将其也包含在虚拟筛选中。虚拟筛选确定了几种预测与 RdRP 的保守 RNA 隧道结合的药物，其中许多提议的靶标都位于其中。在这些候选药物中，奎奴普丁特别有趣，因为它预计会穿过 RNA 隧道结合，从两侧阻断进入，这表明它有可能通过阻止病毒 RNA 合成来阻止病毒复制。奎奴普丁是一种抗生素，已经临床使用了二十年，已知副作用相对较小。奎奴普丁代表了一种有潜力的抗 SARS-CoV-2 治疗方法。目前，我们没有证据表明这种药物对 SARS-CoV-2 有效，但预计生物医学界将迅速跟进我们的研究结果。
