A Comprehensive Protein Interaction Map and Druggability Investigation Prioritized Dengue Virus NS1 Protein as Promising Therapeutic Candidate
Qurrat ul Ain Farooq, Sara Aiman, Yasir Ali, Zeeshan Shaukat, Yasir Ali, Asifullah Khan, Abdus Samad, Abdul Wadood, Chunhua Li
Abstract
Dengue Virus (DENV) is a serious threat to human life worldwide and is one of the most dangerous vector-borne diseases, causing thousands of deaths annually. We constructed a comprehensive PPI map of DENV with its host Homo sapiens and performed various bioinformatics analyses. We found 1195 interactions between 858 human and 10 DENV proteins. Pathway enrichment analysis was performed on the two sets of gene products, and the top 5 human proteins with the maximum number of interactions with dengue viral proteins revealed noticeable results.
Introduction
Dengue is a vector-borne disease transmitted by mosquitoes, and it is currently the most serious arboviral infection, infecting approximately 400 million people worldwide annually, causing 25000 deaths every year [1–3]. In 2012, the World Health Organization (WHO) declared dengue as the most important mosquito-borne viral disease in the world, and despite the fact that it is of worldwide concern, 75% of the cases affected by dengue resided in the Asia-Pacific region [4, 5]. Dengue fever is endemic to Pakistan and is transmitted year-round with seasonal peaks. However, the number of recorded dengue cases is much higher in 2022 (between January and September) due to the worst floods in the country which started in mid-June. In Pakistan, 22,938 cases of dengue fever were recorded in 2017, more than 3,200 cases in 2018, 24,547 cases in 2019, and 3,442 cases in 2020, according to the National Institute of Health (NIH) in Islamabad.
Material and methods
Protein-protein interaction (PPI) data collection
PubMed Advanced search featuring multiple keywords was used to gather all the data available on protein-protein interactions of DENV with its host, Homo sapiens. Out of the total 1254 results, we found our desired data in the 21 studies that exclusively contained PPI data of DENV-DENV and DENV-human. The data collected from these 21 studies were merged, we got 1195 unique interactions after removing duplicates. Table 1 lists the selected studies with their respective number of identified interactions.The interaction data collected in this study include only physical and direct interactions between DENV and human proteins, and have been verified by experimental methods, including Yeast 2 Hybrid (Y2H), Coimmunoprecipitation, mass spectrometry, GST pull-down assay, and co-transfection. The UniProt ID Mapping tool was employed to ensure that the network file loaded into Cytoscape has uniform data.
Results
DENV-human protein-protein interaction network
The PPI networks of DENV-DENV and DENV-human constructed in Cytoscape are shown in Fig 1A. The network was explored using network analyzer, that is capable of computing the average number of neighbors a node (protein) has in the network, the diameter of the network, and the high-scoring proteins in the network. It can also compute network density based on the total number of proteins and their interactions in the network. The statistical information for the current DENV protein interaction network is presented in Table 2.
Discussion
The results explained in the previous sections of this study reveal that the top 5 and 30 highly dengue-associated gene products are enriched in various other pathways, indicating that these proteins are not well studied in dengue viral infections. The top 5 proteins with the highest number of interactions with dengue proteins in the network were associated with another insect-borne disease, African trypanosmiasis. Other disease pathways included malaria, mitophagy, and prostate cancer. Enrichment analysis of the gene sets reveals that the Dengue fever is not the only disease in which the genes are actively involved. HBA1, UBE2I, CSNK2A1, RRP12, and HSP90AB1 were highly enriched in African trypanosmiasis (sleeping sickness) than in the dengue viral infection pathway.
Conclusions
In this study, we adopted state-of-the-art system biology techniques with molecular docking and molecular dynamic simulations to identify druggable protein candidates for DENV. A protein interaction map of the dengue virus and associated host proteins was constructed from experimental data. KEGG pathway and gene ontology analyses of the highly Dengue virus-associated human proteins identified proteins involved in biological processes targeted by the virus. The DENV-NS1 protein was prioritized as a druggable protein based on the highest number of interactions with the human host.
Acknowledgments
The authors thank Dr. Chunhua Li from Beijing University of Technology, China for providing technical support and supervising this research.
Citation: Farooq QuA, Aiman S, Ali Y, Shaukat Z, Ali Y, Khan A, et al. (2023) A comprehensive protein interaction map and druggability investigation prioritized dengue virus NS1 protein as promising therapeutic candidate. PLoS ONE 18(7): e0287905. https://doi.org/10.1371/journal.pone.0287905
Editor: Sheikh Arslan Sehgal, The Islamia University of Bahawalpur Pakistan, PAKISTAN
Received: January 17, 2023; Accepted: June 15, 2023; Published: July 27, 2023
Copyright: © 2023 Farooq et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work is supported by National Natural Science Foundation of China [31971180].
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: DENV, Dengue Virus; C, Capsid protein; E, Envelope protein; M, Membrane protein; NS1, Non-structural protein 1; NS2A, Non-structural protein 2A; NS2B, Non-structural protein 2B; NS3, Non-structural protein 3; NS4A, Non-structural protein 4A; NS4B, Non-structural protein 4B; NS5, Non-structural protein 5; HBA1, Hemoglobin alpha locus 1; UBE2I, Ubiquitin Conjugating Enzyme E2 I; PPI, Protein-Protein Interaction; KEGG, Kyoto Encyclopedia of Genes and Genomics
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0287905#abstract0
