1 INTRODUCTION

The current pandemic of coronavirus disease 2019 (COVID‐19) poses a threat to global public health owing to its high rate of spread and its association with severe forms of respiratory infection, including pneumonia.^1-3 It is characterized by an exaggerated immune response (cytokine storm) with high TNF‐α levels, among other cytokines. It has a high risk of mortality in the older population with cardiovascular (coronary artery disease, heart failure, and cardiac arrhythmias) and pulmonary (chronic obstructive pulmonary disease) comorbidities.⁴

COVID‐19 is transmitted from person to person by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a single‐stranded positive‐sense RNA virus. The SARS‐CoV‐2 genome shows a 5′ untranslated region (UTR), replicase enzyme coding region, S gene, E gene, M gene, N gene, 3′ UTR, and several unidentified nonstructural open reading frames.⁵

This genome encodes four main structural proteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins. The S protein is the receptor‐binding site on the viral surface; the M protein shapes the virions, promotes membrane curvature, and is responsible for the transport of nutrients across cell membranes; the E protein plays a role in the assembly and release of the virus, and is involved in viral pathogenesis; and the N protein can bind to the viral RNA genome and maintain its stability.^{6, 7}

The current pharmacological strategies against COVID‐19 are based on improve the immune responses to SARS‐CoV‐2 and prevent its severe complications.⁶ To date, there are no clinically approved antibodies or drugs specific for SARS‐CoV‐2, making the control of the associated pandemic difficult; therefore, health services are limited to monitoring and containment of the virus. This situation requires the development of safe and effective treatments, and investigation into the history of treatments for similar outbreaks is necessary to extrapolate potential antiviral therapies.^1-3

SARS‐CoV‐2 shares phylogenetic traits with SARS‐CoV and MERS‐CoV; therefore, antiviral treatments effective against these viruses may provide some insight into the development of therapeutics for COVID‐19. Due to the nature of the pandemic, priority is being given to FDA‐approved drugs or clinical trial candidates in Phase III that are close to being commercialized.^1-3 Also, the immunotherapies may be effective in the early stages of infection. The use of convalescent plasma, intravenous immunoglobulin, and monoclonal antibodies can provide virus‐neutralizing and inhibition effects. The lung damage of COVID‐19 is, at least partially, mediated by the immune response against the virus, and it is theoretically possible that modulating that inflammation by TNF‐α, IL‐17, and IL‐23 inhibition might even be protective.^{4, 8}

中文翻译：

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SARS-CoV-2 病毒感染：靶标和抗病毒药理学策略

1 简介

当前的 2019 年冠状病毒病 (COVID-19) 大流行对全球公共卫生构成威胁，因为它的传播率很高，并且与包括肺炎在内的严重呼吸道感染有关。^1-3它的特点是具有高 TNF-α 水平和其他细胞因子的夸大免疫反应（细胞因子风暴）。在患有心血管疾病（冠状动脉疾病、心力衰竭和心律失常）和肺部疾病（慢性阻塞性肺疾病）的老年人群中，它具有很高的死亡风险。^4个

COVID-19 通过严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 在人与人之间传播，SARS-CoV-2 是一种单链正链 RNA 病毒。SARS-CoV-2 基因组显示一个 5' 非翻译区 (UTR)、复制酶编码区、S 基因、E 基因、M 基因、N 基因、3' UTR 和几个未识别的非结构开放阅读框。^5个

该基因组编码四种主要结构蛋白：刺突蛋白 (S)、膜蛋白 (M)、包膜蛋白 (E) 和核衣壳蛋白 (N)。S 蛋白是病毒表面的受体结合位点；M 蛋白塑造病毒粒子，促进膜弯曲，并负责营养物质跨细胞膜的运输；E蛋白参与病毒的组装和释放，参与病毒的发病机制；N蛋白可以与病毒RNA基因组结合并保持其稳定性。^{6, 7}

目前针对 COVID-19 的药理学策略是基于提高对 SARS-CoV-2 的免疫反应并预防其严重并发症。⁶迄今为止，尚无临床批准的针对 SARS-CoV-2 的抗体或药物，这使得控制相关大流行变得困难；因此，卫生服务仅限于监测和遏制病毒。这种情况需要开发安全有效的治疗方法，并且有必要调查类似暴发的治疗历史以推断潜在的抗病毒疗法。^1-3

SARS-CoV-2 与 SARS-CoV 和 MERS-CoV 具有相同的系统发育特征；因此，对这些病毒有效的抗病毒治疗可能会为 COVID-19 的治疗方法的发展提供一些见解。由于大流行的性质，优先考虑 FDA 批准的处于 III 期且即将商业化的药物或临床试验候选药物。^1-3此外，免疫疗法可能在感染的早期阶段有效。使用恢复期血浆、静脉注射免疫球蛋白和单克隆抗体可以提供病毒中和和抑制作用。COVID-19 的肺损伤至少部分是由针对病毒的免疫反应介导的，从理论上讲，通过抑制 TNF-α、IL-17 和 IL-23 来调节炎症甚至可能具有保护作用。^{4, 8}