Virology Drug Discovery, AbbVie Inc., North Chicago, IL 60064, USA.
Department of Cell and Protein Sciences, Drug Discovery Science and Technology, AbbVie Inc., Worcester, MA 01605, USA.
Viruses. 2022 May 4;14(5):961. doi: 10.3390/v14050961.
The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex.
2019 年冠状病毒病（COVID-19）大流行是由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起的，这是一种新出现的人类冠状病毒。COVID-19 疫苗已被证明能有效保护接种者免受感染，减轻疾病严重程度，并阻止感染传播。然而，COVID-19 疫苗接种面临许多挑战，例如随着时间的推移疫苗诱导的免疫力下降，以及对一些 SARS-CoV-2 变种（包括最近出现的奥密克戎变种）效力降低，导致突破性感染。COVID-19 疫苗接种面临的挑战凸显了发现抗病毒药物作为应对大流行的另一种手段的重要性。迄今为止，针对病毒刺突蛋白的中和抗体已成为最大的一类抗病毒药物，这些药物已获得美国食品和药物管理局（FDA）对 COVID-19 治疗的紧急使用授权（EUA）。除了刺突蛋白，其他用于发现直接作用抗病毒药物的关键靶点包括对 SARS-CoV-2 复制至关重要的病毒酶，如 RNA 依赖性 RNA 聚合酶和蛋白酶，这从美国 FDA 对瑞德西韦的批准和 EUA 对治疗 COVID-19 感染的帕罗维德（nirmatrelvir + ritonavir）中可以看出。这篇综述介绍了治疗 SARS-CoV-2 感染的抗病毒药物发现的现状和未来方向，涵盖了重要的抗病毒靶点，如病毒刺突蛋白、非结构蛋白（nsp）3 木瓜蛋白酶样蛋白酶、nsp5 主蛋白酶和 nsp12/nsp7/nsp8 RNA 依赖性 RNA 聚合酶复合物。
