The paramyxovirus polymerase complex as a target for next-generation anti-paramyxovirus therapeutics.
The paramyxovirus polymerase complex as a target for next-generation anti-paramyxovirus therapeutics.
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参氧病毒聚合酶复合物是下一代抗paramyxovirus疗法的靶标。
DOI：
10.3389/fmicb.2015.00459
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发表时间：
2015
影响因子：
5.2
通讯作者：
Plemper RK
中科院分区：
文献类型：
--
作者：
Cox R;Plemper RK
副粘病毒家族包括主要的人类和动物病原体，包括麻疹病毒、腮腺炎病毒和人类呼吸道合胞病毒（RSV），以及新兴的人畜共患亨德拉病毒和尼帕病毒。在美国，RSV是婴儿因病毒感染性疾病住院的主要原因。尽管其临床意义，有效的药物，改善副粘病毒病的管理是缺乏的。因此，迫切需要开发新的抗副粘病毒治疗剂。副粘病毒含有负极性的RNA基因组，需要病毒编码的RNA依赖性RNA聚合酶（RdRp）复合物进行复制和转录。由于宿主细胞中不存在等效的酶活性，RdRp复合物代表了一个有吸引力的可药用靶标，尽管缺乏高分辨率RdRp晶体结构阻碍了结构指导的药物开发活动。在这里，我们回顾了目前的副粘病毒聚合酶复合物的结构和功能的洞察力，结合可用的实验RdRp抑制剂的活性和发展状况的机制的评价。我们的评估突出了RdRp复合物作为治疗干预的首要目标的重要性，并研究了对复合物组织的高分辨率洞察将如何为急需的下一代副粘病毒RdRp阻断剂的结构指导设计和优化铺平道路。
The paramyxovirus family includes major human and animal pathogens, including measles virus, mumps virus, and human respiratory syncytial virus (RSV), as well as the emerging zoonotic Hendra and Nipah viruses. In the U.S., RSV is the leading cause of infant hospitalizations due to viral infectious disease. Despite their clinical significance, effective drugs for the improved management of paramyxovirus disease are lacking. The development of novel anti-paramyxovirus therapeutics is therefore urgently needed. Paramyxoviruses contain RNA genomes of negative polarity, necessitating a virus-encoded RNA-dependent RNA polymerase (RdRp) complex for replication and transcription. Since an equivalent enzymatic activity is absent in host cells, the RdRp complex represents an attractive druggable target, although structure-guided drug development campaigns are hampered by the lack of high-resolution RdRp crystal structures. Here, we review the current structural and functional insight into the paramyxovirus polymerase complex in conjunction with an evaluation of the mechanism of activity and developmental status of available experimental RdRp inhibitors. Our assessment spotlights the importance of the RdRp complex as a premier target for therapeutic intervention and examines how high-resolution insight into the organization of the complex will pave the path toward the structure-guided design and optimization of much-needed next-generation paramyxovirus RdRp blockers.