Xu Eric, Park Seohyun, Calderon Juan, Cao Dongdong, Liang Bo
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
Microorganisms. 2023 Jun 18;11(6):1608. doi: 10.3390/microorganisms11061608.
Respiratory Syncytial Virus (RSV) is the top cause of infant hospitalization globally, with no effective treatments available. Researchers have sought small molecules to target the RNA-dependent RNA Polymerase (RdRP) of RSV, which is essential for replication and transcription. Based on the cryo-EM structure of the RSV polymerase, in silico computational analysis including molecular docking and the protein-ligand simulation of a database, including 6554 molecules, is currently undergoing phases 1-4 of clinical trials and has resulted in the top ten repurposed compound candidates against the RSV polymerase, including Micafungin, Totrombopag, and Verubecestat. We performed the same procedure to evaluate 18 small molecules from previous studies and chose the top four compounds for comparison. Among the top identified repurposed compounds, Micafungin, an antifungal medication, showed significant inhibition and binding affinity improvements over current inhibitors such as ALS-8112 and Ribavirin. We also validated Micafungin's inhibition of the RSV RdRP using an in vitro transcription assay. These findings contribute to RSV drug development and hold promise for broad-spectrum antivirals targeting the non-segmented negative-sense (NNS) RNA viral polymerases, including those of rabies (RABV) and Ebola (EBOV).
呼吸道合胞病毒（RSV）是全球婴儿住院的首要原因，目前尚无有效的治疗方法。研究人员一直在寻找能够靶向RSV的RNA依赖性RNA聚合酶（RdRP）的小分子，该酶对于病毒复制和转录至关重要。基于RSV聚合酶的冷冻电镜结构，包括分子对接和对一个包含6554个分子的数据库进行蛋白质-配体模拟的计算机模拟分析，目前正处于临床试验的1-4期，已产生了针对RSV聚合酶的十大重新利用的化合物候选物，包括米卡芬净、托特罗莫帕格和维鲁比西他。我们对先前研究中的18种小分子进行了同样的评估程序，并选择了前四种化合物进行比较。在确定的顶级重新利用化合物中，抗真菌药物米卡芬净比目前的抑制剂如ALS-8112和利巴韦林表现出显著的抑制作用和结合亲和力的提高。我们还使用体外转录试验验证了米卡芬净对RSV RdRP的抑制作用。这些发现有助于RSV药物的开发，并为针对非节段性负链（NNS）RNA病毒聚合酶的广谱抗病毒药物带来希望，包括狂犬病病毒（RABV）和埃博拉病毒（EBOV）的聚合酶。
