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靶向SARS-CoV-2 RNA抗病毒小分子药物研究进展

Recent advances in RNA-targeted antiviral agents against SARS-CoV-2

  • 摘要: 针对SARS-CoV-2的抗病毒药物研发是防治新冠病毒感染的主要策略。现有的抗SARS-CoV-2药物主要针对病毒生命周期中的关键蛋白靶点,如主蛋白酶(Mpro)、木瓜样蛋白酶(PLpro)、RNA依赖的RNA聚合酶(RdRp)等,这些药物尚不足以应对新冠病毒突变快、易产生耐药等挑战。近年来,病毒RNA已被证明是极具潜力的药物靶点。靶向病毒RNA的小分子药物具有显著优势,其作用机制新颖,具备广谱抗病毒与克服耐药性的潜力,为应对冠状病毒威胁提供了新途径。本综述系统总结了靶向SARS-CoV-2保守RNA元件,如移码刺激元件(FSE)、茎环结构(SL)及G-四链体(G-4)的小分子抑制剂,以及RNA靶向嵌合体(RNATAC)的最新研究进展,旨在为靶向SARS-CoV-2 RNA的抗病毒小分子药物研发提供参考。

     

    Abstract: The development of antiviral drugs targeting SARS-CoV-2 remains a major strategy for the prevention and treatment of COVID-19 infection. Current anti-SARS-CoV-2 agents mainly act on key viral protein targets involved in the viral life cycle, such as the main protease (Mpro), papain-like protease (PLpro), and RNA-dependent RNA polymerase (RdRp). However, these drugs are insufficient to address the challenges posed by the rapid mutation rate and drug resistance of SARS-CoV-2. In recent years, viral RNA has demonstrated to be a highly promising therapeutic target. Small-molecule drugs that target viral RNA possess distinct advantages, featuring novel mechanisms of action and the potential for broad-spectrum antiviral activity as well as the ability to overcome drug resistance. Such agents provide a new avenue for combating coronavirus threats. This review systematically summarizes recent advances in the development of small-molecule inhibitors targeting conserved SARS-CoV-2 RNA structures, including the frameshift stimulation element (FSE), stem-loops (SL), G-quadruplexes (G-4), and RNA-targeting chimeras (RNATAC), aiming to provide some insight to guide future.

     

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