Abstract
Influenza A viruses still represent a major health issue, for both humans and animals. One of the main viral proteins of interest to target is the NS1 protein, which counters the host immune response and promotes viral replication. NS1 is a homodimer composed of a dimeric RNA-binding domain (RBD), which is structurally stable and conserved in sequence, and two effector domains that are tethered to the RBD by linker regions. This linker flexibility leads to NS1 polymorphism and can therefore exhibit different forms. Previously, we identified a putative drug-binding site, located in the RBD interface in a crystal structure of NS1. This pocket could be targeted to block RNA binding and inhibit NS1 activities. The objective of the present study is to confirm the presence of this druggable site, whatever the sequence variants, in order to develop a universal therapeutic compound that is insensitive to sequence variations and structural flexibility. Using a set of four NS1 full-length structures, we combined different bioinformatics approaches such as pocket tracking along molecular dynamics simulations, druggability prediction and classification. This protocol successfully confirmed a frequent large binding-site that is highly druggable and shared by different NS1 forms, which is promising for developing a robust NS1-targeted therapy.
Funder
doctoral school “Pierre Louis de santé publique”
Université Paris Cité
CNRS institute
INSERM institute
Subject
Molecular Biology,Biochemistry
Reference49 articles.
1. Zhao, M., Wang, L., and Li, S. (2017). Influenza A Virus–Host Protein Interactions Control Viral Pathogenesis. Int. J. Mol. Sci., 18.
2. (2021, December 20). Influenza (Seasonal). Available online: https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal).
3. Estimates of US influenza-associated deaths made using four different methods;Thompson;Influenza Other Respir. Viruses,2009
4. The pathogenesis of influenza virus infections: The contributions of virus and host factors;Fukuyama;Curr. Opin. Immunol.,2011
5. Inefficient Control of Host Gene Expression by the 2009 Pandemic H1N1 Influenza A Virus NS1 Protein;Hale;J. Virol.,2010
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献