Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States.
Curr Med Chem. 2019;26(13):2243-2263. doi: 10.2174/0929867325666180706112940.
Influenza viruses are severe human pathogens that pose persistent threat to public health. Each year more people die of influenza virus infection than that of breast cancer. Due to the limited efficacy associated with current influenza vaccines, as well as emerging drug resistance from small molecule antiviral drugs, there is a clear need to develop new antivirals with novel mechanisms of action. The influenza virus polymerase complex has become a promising target for the development of the next-generation of antivirals for several reasons. Firstly, the influenza virus polymerase, which forms a heterotrimeric complex that consists of PA, PB1, and PB2 subunits, is highly conserved. Secondly, both individual polymerase subunit (PA, PB1, and PB2) and inter-subunit interactions (PA-PB1, PB1- PB2) represent promising drug targets. Lastly, growing insight into the structure and function of the polymerase complex has spearheaded the structure-guided design of new polymerase inhibitors. In this review, we highlight recent progress in drug discovery and assay development targeting the influenza virus polymerase complex and discuss their therapeutic potentials.
流感病毒是严重的人类病原体，对公共卫生构成持续威胁。每年死于流感病毒感染的人数多于死于乳腺癌的人数。由于目前流感疫苗的效果有限，以及小分子抗病毒药物出现耐药性，显然需要开发具有新作用机制的新型抗病毒药物。流感病毒聚合酶复合物已成为开发下一代抗病毒药物的有希望的靶标，原因有几个。首先，形成由 PA、PB1 和 PB2 亚基组成的异源三聚体复合物的流感病毒聚合酶高度保守。其次，单个聚合酶亚基（PA、PB1 和 PB2）和亚基间相互作用（PA-PB1、PB1-PB2）都代表有前途的药物靶点。最后，对聚合酶复合物结构和功能的深入了解推动了基于结构的新型聚合酶抑制剂的设计。在这篇综述中，我们强调了针对流感病毒聚合酶复合物的药物发现和测定开发的最新进展，并讨论了它们的治疗潜力。
