Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore-632014, Tamil Nadu, India.
Department of Clinical Virology, Christian Medical College, Tamil Nadu, Vellore, 632004, India.
BMC Infect Dis. 2024 May 10;24(1):483. doi: 10.1186/s12879-024-09332-x.
Monkeypox (Mpox) is an important human pathogen without etiological treatment. A viral-host interactome study may advance our understanding of molecular pathogenesis and lead to the discovery of suitable therapeutic targets.
GEO Expression datasets characterizing mRNA profile changes in different host responses to poxviruses were analyzed for shared pathway identification, and then, the Protein-protein interaction (PPI) maps were built. The viral gene expression datasets of Monkeypox virus (MPXV) and Vaccinia virus (VACV) were used to identify the significant viral genes and further investigated for their binding to the library of targeting molecules.
Infection with MPXV interferes with various cellular pathways, including interleukin and MAPK signaling. While most host differentially expressed genes (DEGs) are predominantly downregulated upon infection, marked enrichments in histone modifiers and immune-related genes were observed. PPI analysis revealed a set of novel virus-specific protein interactions for the genes in the above functional clusters. The viral DEGs exhibited variable expression patterns in three studied cell types: primary human monocytes, primary human fibroblast, and HeLa, resulting in 118 commonly deregulated proteins. Poxvirus proteins C6R derived protein K7 and K7R of MPXV and VACV were prioritized as targets for potential therapeutic interventions based on their histone-regulating and immunosuppressive properties. In the computational docking and Molecular Dynamics (MD) experiments, these proteins were shown to bind the candidate small molecule S3I-201, which was further prioritized for lead development.
MPXV circumvents cellular antiviral defenses by engaging histone modification and immune evasion strategies. C6R-derived protein K7 binding candidate molecule S3I-201 is a priority promising candidate for treating Mpox.
猴痘（Mpox）是一种重要的人类病原体，目前尚无病因治疗方法。病毒-宿主相互作用组学研究可能有助于深入了解分子发病机制，并发现合适的治疗靶点。
分析了不同宿主对痘病毒反应的基因表达谱变化的 GEO 表达数据集，以识别共享途径，并构建蛋白质-蛋白质相互作用（PPI）图谱。使用猴痘病毒（MPXV）和牛痘病毒（VACV）的病毒基因表达数据集来识别重要的病毒基因，并进一步研究它们与靶向分子文库的结合情况。
MPXV 感染会干扰包括白细胞介素和 MAPK 信号在内的多种细胞途径。虽然大多数宿主差异表达基因（DEG）在感染后主要下调，但观察到组蛋白修饰物和免疫相关基因的明显富集。PPI 分析揭示了上述功能簇中基因的一组新的病毒特异性蛋白相互作用。病毒 DEG 在三种研究的细胞类型中表现出不同的表达模式：原代人单核细胞、原代人成纤维细胞和 HeLa，导致 118 个共同下调的蛋白质。基于其组蛋白调节和免疫抑制特性，MPXV 和 VACV 的 C6R 衍生蛋白 K7 和 K7R 以及痘病毒蛋白被优先作为潜在治疗干预的靶点。在计算对接和分子动力学（MD）实验中，这些蛋白质被证明与候选小分子 S3I-201 结合，S3I-201 进一步被优先作为先导化合物进行开发。
MPXV 通过参与组蛋白修饰和免疫逃避策略来规避细胞抗病毒防御。C6R 衍生蛋白 K7 结合候选分子 S3I-201 是治疗猴痘的优先有前途的候选药物。
