Hong Junbin, Guo Zhendong, Huang XiaoMei, Wu Peng, Chen Xinying, Liu Xiaoyi, Yang Jinghua, Lai Yanni
Guangzhou University of Chinese Medicine, Guangzhou, China.
School of Medicine and Health, Shunde Polytechnic, Foshan, China.
Front Microbiol. 2025 Apr 30;16:1552603. doi: 10.3389/fmicb.2025.1552603. eCollection 2025.
The clinical consequences of the co-infection with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) are not optimistic. Nevertheless, there is currently no approved therapeutic regimen specifically targeting SARS-CoV-2/RSV co-infection, with existing monotherapies showing limited efficacy. According to recent studies, probenecid has both anti-SARS-CoV-2 and anti-RSV effects. Therefore, as one probable molecular candidate for the co-infection with SARS-CoV-2 and RSV, probenecid was researched in this exploration.
Using systems pharmacology and bioinformatics, we characterized the targets associated with probenecid for the treatment of SARS-CoV-2/RSV co-infection, focusing on their biological functions, mechanisms and binding activities. To further validate these findings, we conducted molecular docking, MD simulations, electrostatic potential mapping, and SAR analysis to explore the binding interactions between probenecid and the identified core targets.
We identified 141 targets that overlapped with the co-infection and probenecid, and used these shared targets to construct a protein-protein interaction (PPI) network. Subsequently, we obtained the top 16 hub targets of probenecid for SARS-CoV-2/RSV co-infection, namely, AKT1, ALB, EGFR, CASP3, CTNNB1, SRC, HSP90AA1, and so on. According to the enrichment analysis, probenecid might affect inflammation, immunity, oxidative stress, and virus defenses; Toll-like receptor, TNF, IL-17, NOD-like receptor, cytokine-cytokine receptor, among others. Additionally, based on molecular docking analysis, probenecid is effectively bound to the targets related to the SARS-CoV-2/RSV co-infection. Meanwhile, according to molecular dynamics (MD) simulations and structure-activity relationship (SAR) analysis, we speculated that SRC and HSP90AA1 are more likely to be the target proteins of probenecid than the other proteins.
Our findings from systems pharmacology and bioinformatics analysis indicate that immune and inflammatory responses play a pivotal role in the therapeutic effects of probenecid. Infectious disease-related pathways also contribute significantly to its effectiveness in treating SARS-CoV-2/RSV co-infection. Further validation was conducted through molecular docking, MD simulations, electrostatic potential mapping, and SAR analysis. These analyses suggest that SRC and HSP90AA1 are the potential binding targets of probenecid. This study provides valuable preliminary insights into the molecular mechanisms of probenecid. It establishes a strong foundation for future research to explore its potential as a therapeutic strategy for SARS-CoV-2/RSV co-infection.
新型严重急性呼吸综合征冠状病毒2（SARS-CoV-2）与呼吸道合胞病毒（RSV）合并感染的临床后果不容乐观。然而，目前尚无专门针对SARS-CoV-2/RSV合并感染的获批治疗方案，现有的单一疗法疗效有限。根据最近的研究，丙磺舒具有抗SARS-CoV-2和抗RSV的作用。因此，作为SARS-CoV-2和RSV合并感染的一种可能的分子候选物，本研究对丙磺舒进行了探索。
我们运用系统药理学和生物信息学方法，对丙磺舒治疗SARS-CoV-2/RSV合并感染相关的靶点进行了表征，重点关注其生物学功能、机制和结合活性。为进一步验证这些发现，我们进行了分子对接、分子动力学模拟、静电势映射和构效关系分析，以探索丙磺舒与已鉴定的核心靶点之间的结合相互作用。
我们鉴定出141个与合并感染和丙磺舒重叠的靶点，并利用这些共享靶点构建了蛋白质-蛋白质相互作用（PPI）网络。随后，我们获得了丙磺舒治疗SARS-CoV-2/RSV合并感染的前16个核心靶点，即AKT1、ALB、EGFR、CASP3、CTNNB1、SRC、HSP90AA1等。根据富集分析，丙磺舒可能影响炎症、免疫、氧化应激和病毒防御；Toll样受体、TNF、IL-17、NOD样受体、细胞因子-细胞因子受体等。此外，基于分子对接分析，丙磺舒与SARS-CoV-2/RSV合并感染相关的靶点有效结合。同时，根据分子动力学（MD）模拟和构效关系（SAR）分析，我们推测SRC和HSP90AA1比其他蛋白质更有可能是丙磺舒的靶蛋白。
我们从系统药理学和生物信息学分析中得到的结果表明，免疫和炎症反应在丙磺舒的治疗效果中起关键作用。与传染病相关的途径对其治疗SARS-CoV-2/RSV合并感染的有效性也有显著贡献。通过分子对接、MD模拟、静电势映射和SAR分析进行了进一步验证。这些分析表明SRC和HSP90AA1是丙磺舒的潜在结合靶点。本研究为丙磺舒的分子机制提供了有价值的初步见解。它为未来探索其作为SARS-CoV-2/RSV合并感染治疗策略的潜力奠定了坚实基础。
