Diogo Marcel Arruda, Cabral Augusto Gomes Teixeira, de Oliveira Renata Barbosa
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
Pathogens. 2024 Sep 24;13(10):825. doi: 10.3390/pathogens13100825.
SARS-CoV-2 is a spherical, positive-sense, single-stranded RNA virus with a large genome, responsible for encoding both structural proteins, vital for the viral particle's architecture, and non-structural proteins, critical for the virus's replication cycle. Among the non-structural proteins, two cysteine proteases emerge as promising molecular targets for the design of new antiviral compounds. The main protease (M) is a homodimeric enzyme that plays a pivotal role in the formation of the viral replication-transcription complex, associated with the papain-like protease (PL), a cysteine protease that modulates host immune signaling by reversing post-translational modifications of ubiquitin and interferon-stimulated gene 15 (ISG15) in host cells. Due to the importance of these molecular targets for the design and development of novel anti-SARS-CoV-2 drugs, the purpose of this review is to address aspects related to the structure, mechanism of action and strategies for the design of inhibitors capable of targeting the M and PL. Examples of covalent and non-covalent inhibitors that are currently being evaluated in preclinical and clinical studies or already approved for therapy will be also discussed to show the advances in medicinal chemistry in the search for new molecules to treat COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是一种球形、正链、单链RNA病毒，基因组庞大，负责编码对病毒颗粒结构至关重要的结构蛋白以及对病毒复制周期至关重要的非结构蛋白。在非结构蛋白中，两种半胱氨酸蛋白酶成为设计新型抗病毒化合物的有前景的分子靶点。主要蛋白酶（M）是一种同源二聚体酶，在病毒复制转录复合体的形成中起关键作用，它与木瓜样蛋白酶（PL）相关，木瓜样蛋白酶是一种半胱氨酸蛋白酶，通过逆转宿主细胞中泛素和干扰素刺激基因15（ISG15）的翻译后修饰来调节宿主免疫信号。由于这些分子靶点对新型抗SARS-CoV-2药物的设计和开发至关重要，本综述的目的是探讨与能够靶向M和PL的抑制剂的结构、作用机制及设计策略相关的方面。还将讨论目前正在临床前和临床研究中评估或已获批用于治疗的共价和非共价抑制剂的实例，以展示药物化学在寻找治疗新冠肺炎新分子方面的进展。
