Druggable Pockets at the RNA Interface Region of Influenza A Virus NS1 Protein Are Conserved across Sequence Variants from Distinct Subtypes - Archive ouverte HAL Access content directly
Journal Articles Biomolecules Year : 2023

Druggable Pockets at the RNA Interface Region of Influenza A Virus NS1 Protein Are Conserved across Sequence Variants from Distinct Subtypes

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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.
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Dates and versions

hal-03927052 , version 1 (17-01-2023)

Licence

Attribution - CC BY 4.0

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Sarah Naceri, Daniel Marc, Rachel Blot, Delphine Flatters, Anne-Claude Camproux. Druggable Pockets at the RNA Interface Region of Influenza A Virus NS1 Protein Are Conserved across Sequence Variants from Distinct Subtypes. Biomolecules, 2023, 13 (1), pp.64. ⟨10.3390/biom13010064⟩. ⟨hal-03927052⟩
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