Selecting monkeypox virus drug targets and antiviral drugs based on protein-protein interaction networks

Objective Construct a protein interaction network between monkeypox virus (MPXV) and humans. Through the analysis of this network, identify monkeypox virus proteins and human proteins as potential drug targets, and predict antiviral drugs.Methods The interaction network between MPXV and human proteins (MIP) was established based on the P-HIPSTer database. MPXV proteins in the established interaction network were selected as drug targets by calculating the centrality, conservation, and immunogenicity of virus proteins. A protein interaction network was established between MIP and human proteins. Through the analysis of network topology properties, the most important MIP (abbreviated as MMIP) were identified as potential drug targets. An interaction network between MIP and other viruses was established, and within MMIP, broad-spectrum drug target proteins were further screened. Functional enrichment of MIP genes was conducted using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, performed with the “clusterProfiler” package in R. Finally, drugs targeting MPXV and human proteins identified in the above steps were predicted based on the DrugBank database.Results The protein interaction network between MPXV and humans was constructed, which contained 4591 non-redundant protein-protein interactions between 70 virus proteins and 2,218 human proteins (abbreviated as MIP). Three MPXV proteins, OPG083, OPG084, and OPG190, were identified as drug targets. The 86 the most important MIPs (MMIPs) were selected as potential drug target. An interaction network between MIP and proteins from other viruses revealed 31 MMIPs as potential broad-spectrum drug targets. Functional analysis of MIP indicated enrichment in infection and immune system pathways. A total of 85 drugs were identified to act on MPXV proteins, and 371 drugs on human proteins. Among them, fostamatinib, trilostane and raloxifen are capable of simultaneously inhibiting both virus and host proteins in the interaction network between MPXV and humans.Conclusion A protein interaction network between MPXV and humans was established. OPG083, OPG084, and OPG190 were identified as drug targets, while 31 human proteins were recognized as potential targets against MPXV. A total of 453 drugs were predicted to inhibit virus infection by disrupting the virus-host interaction protein-protein interaction (PPI) network, with priority given to validating drugs such as fostamatinib, trilostane and raloxifen.

研究目标 构建猴痘病毒（monkeypox virus, MPXV）与人类之间的蛋白质相互作用网络。通过对该网络的分析，筛选可作为潜在药物靶点的猴痘病毒蛋白与人类蛋白，并预测抗病毒药物。
研究方法 基于P-HIPSTer数据库构建MPXV与人类蛋白质的相互作用网络（MIP）。通过计算病毒蛋白的中心性、保守性与免疫原性，从已构建的互作网络中筛选出可作为药物靶点的MPXV蛋白。进一步构建MIP与人类蛋白质的相互作用网络，通过分析网络拓扑属性，识别其中最为关键的MIP（简称MMIP）作为潜在药物靶点。此外，构建MIP与其他病毒蛋白的相互作用网络，并在MMIP中进一步筛选广谱药物靶点蛋白。采用R语言的"clusterProfiler"包进行基因本体（Gene Ontology, GO）和京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集分析，以完成MIP基因的功能富集注释。最后，基于DrugBank数据库，预测上述步骤中筛选出的靶向MPXV蛋白与人类蛋白的药物。
研究结果 成功构建了MPXV与人类的蛋白质相互作用网络，该网络包含70种病毒蛋白与2218种人类蛋白之间的4591条非冗余蛋白质-蛋白质相互作用（即MIP）。共筛选出3种MPXV蛋白OPG083、OPG084与OPG190作为药物靶点。选取86个最为关键的MIP（即MMIP）作为潜在药物靶点。通过构建MIP与其他病毒蛋白的相互作用网络，发现其中31个MMIP可作为潜在广谱药物靶点。对MIP基因的功能分析显示，其显著富集于感染与免疫系统相关通路。共鉴定出85种可作用于MPXV蛋白的药物，以及371种可作用于人类蛋白的药物。其中，fostamatinib、trilostane与raloxifen可同时抑制MPXV与人类互作网络中的病毒蛋白与宿主蛋白。
研究结论 本研究成功构建了MPXV与人类的蛋白质相互作用网络。鉴定出OPG083、OPG084与OPG190为MPXV药物靶点，同时识别出31种人类蛋白作为抗MPXV的潜在靶点。共预测出453种可通过破坏病毒-宿主蛋白质相互作用（PPI）网络以抑制病毒感染的药物，建议优先验证fostamatinib、trilostane与raloxifen等候选药物。