Department of Infectious Diseases, University of Georgia, Athens, GA 30602, USA.
TrippBio, Inc., Jacksonville, FL 32256, USA.
Int J Mol Sci. 2024 Nov 20;25(22):12452. doi: 10.3390/ijms252212452.
We examined the effect of probenecid in regulating the ERK and JNK downstream MAPK pathways affecting respiratory syncytial virus replication.
We have previously shown that probenecid inhibits RSV, influenza virus, and SARS-CoV-2 replication in vitro in preclinical animal models and in humans. In a Phase two randomized, placebo-controlled, single-blind, dose range-finding study using probenecid to treat non-hospitalized patients with symptomatic, mild-to-moderate COVID-19, we previously showed that a 1000 mg twice daily treatment for 5 days reduced the median time to viral clearance from 11 to 7 days, and a 500 mg twice daily treatment for 5 days reduced the time to viral clearance from 11 to 9 days more than the placebo.
In this study, we sought to determine the mechanism of action of the probenecid inhibition of RSV replication in human respiratory epithelial (A549) cells.
We show that probenecid inhibits the RSV-induced phosphorylation of JNKs and ERKs and the downstream phosphorylation of c-jun, a component of the AP-1 transcription complex needed for virus replication. The inhibition of JNKs by probenecid reversed the repression of transcription factor HNF-4.
The probenecid inhibition of JNK and ERK phosphorylation involves the MAPK pathway that precludes virus replication.
我们研究了丙磺舒对 ERK 和 JNK 下游 MAPK 通路的调节作用，这些通路影响呼吸道合胞病毒的复制。
我们之前已经表明，丙磺舒在临床前动物模型和人类中能够抑制 RSV、流感病毒和 SARS-CoV-2 的复制。在一项使用丙磺舒治疗有症状的轻症至中度 COVID-19 的非住院患者的 II 期随机、安慰剂对照、单盲、剂量范围发现研究中，我们之前表明，1000mg 每日两次治疗 5 天可将病毒清除中位时间从 11 天缩短至 7 天，而 500mg 每日两次治疗 5 天可将病毒清除中位时间从 11 天缩短至 9 天，优于安慰剂。
在这项研究中，我们试图确定丙磺舒抑制人呼吸道上皮（A549）细胞中 RSV 复制的作用机制。
我们表明，丙磺舒抑制 RSV 诱导的 JNKs 和 ERKs 的磷酸化以及病毒复制所需的 AP-1 转录复合物的组成部分 c-jun 的下游磷酸化。丙磺舒对 JNKs 的抑制逆转了转录因子 HNF-4 的抑制。
丙磺舒抑制 JNK 和 ERK 磷酸化涉及 MAPK 通路，从而阻止病毒复制。
