Department of Pediatrics, Johns Hopkins University, School of Medicine, MD, USA.
Department of Botany, Nabadwip Vidyasagar College, Nabadwip, India.
J Biomed Inform. 2021 Jun;118:103801. doi: 10.1016/j.jbi.2021.103801. Epub 2021 May 7.
Understanding the molecular mechanism of COVID-19 pathogenesis helps in the rapid therapeutic target identification. Usually, viral protein targets host proteins in an organized fashion. The expression of any viral gene depends mostly on the host translational machinery. Recent studies report the great significance of codon usage biases in establishing host-viral protein-protein interactions (PPI). Exploring the codon usage patterns between a pair of co-evolved host and viral proteins may present novel insight into the host-viral protein interactomes during disease pathogenesis. Leveraging the similarity in codon usage patterns, we propose a computational scheme to recreate the host-viral protein-protein interaction network. We use host proteins from seventeen (17) essential signaling pathways for our current work towards understanding the possible targeting mechanism of SARS-CoV-2 proteins. We infer both negatively and positively interacting edges in the network. Further, extensive analysis is performed to understand the host PPI network topologically and the attacking behavior of the viral proteins. Our study reveals that viral proteins mostly utilize codons, rare in the targeted host proteins (negatively correlated interaction). Among them, non-structural proteins, NSP3 and structural protein, Spike (S), are the most influential proteins in interacting with multiple host proteins. While ranking the most affected pathways, MAPK pathways observe to be the worst affected during the SARS-CoV-2 infection. Several proteins participating in multiple pathways are highly central in host PPI and mostly targeted by multiple viral proteins. We observe many potential targets (host proteins) from the affected pathways associated with the various drug molecules, including Arsenic trioxide, Dexamethasone, Hydroxychloroquine, Ritonavir, and Interferon beta, which are either under clinical trial or in use during COVID-19.
了解 COVID-19 发病机制的分子机制有助于快速确定治疗靶点。通常，病毒蛋白以有组织的方式靶向宿主蛋白。任何病毒基因的表达主要依赖于宿主翻译机制。最近的研究报告表明，密码子使用偏性在建立宿主-病毒蛋白-蛋白相互作用（PPI）方面具有重要意义。探索一对共进化的宿主和病毒蛋白之间的密码子使用模式，可以为疾病发病过程中的宿主-病毒蛋白互作组提供新的见解。利用密码子使用模式的相似性，我们提出了一种计算方案来重建宿主-病毒蛋白相互作用网络。我们使用来自 17 个（17）必需信号通路的宿主蛋白来进行我们目前的工作，以了解 SARS-CoV-2 蛋白的可能靶向机制。我们推断网络中存在负相互作用和正相互作用边缘。此外，还进行了广泛的分析来了解宿主 PPI 网络的拓扑结构和病毒蛋白的攻击行为。我们的研究表明，病毒蛋白主要利用宿主蛋白中罕见的密码子（负相关相互作用）。其中，非结构蛋白 NSP3 和结构蛋白 Spike（S）是与多个宿主蛋白相互作用的最具影响力的蛋白。在对受影响途径进行排名时，MAPK 途径在 SARS-CoV-2 感染过程中观察到受影响最严重。参与多个途径的多个蛋白质在宿主 PPI 中处于高度中心位置，并且大多被多个病毒蛋白靶向。我们观察到来自受影响途径的许多潜在靶标（宿主蛋白）与各种药物分子（包括三氧化二砷、地塞米松、羟氯喹、利托那韦和干扰素-β）相关联，这些药物分子要么正在临床试验中，要么在 COVID-19 期间使用。
