NS1 protein as a novel anti-influenza target: Map-and-mutate antiviral rationale reveals new putative druggable hot spots with an important role on viral replication

Trigueiro-Louro, João; Santos, Luís A.; Almeida, Filipe; Correia, Vanessa; Brito, Rui M.M.; Rebelo-de-Andrade, Helena

http://hdl.handle.net/10400.18/8564

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Authors

Trigueiro-Louro, João

Rebelo-de-Andrade, Helena

Abstract(s)

Influenza NS1 is a promising anti-influenza target, considering its conserved and druggable structure, and key function in influenza replication and pathogenesis. Notwithstanding, target identification and validation, strengthened by experimental data, are lacking. Here, we further explored our previously designed structure-based antiviral rationale directed to highly conserved druggable NS1 regions across a broad spectrum of influenza A viruses. We aimed to identify NS1-mutated viruses exhibiting a reduced growth phenotype and/or an altered cell apoptosis profile. We found that NS1 mutations Y171A, K175A (consensus druggable pocket 1), W102A (consensus druggable pocket 3), Q121A and G184P (multiple consensus druggable pockets) - located at hot spots amenable for pharmacological modulation - significantly impaired A(H1N1)pdm09 virus replication, in vitro. This is the first time that NS1-K175A, -W102A, and -Q121A mutations are characterized. Our map-and-mutate strategy provides the basis to establish the NS1 as a promising target using a rationale with a higher resilience to resistance development.

Highlights: Structure-based anti-influenza strategies that facilitate the rapid identification and validation of robust targets are lacking; We have previously identified and characterized 3 NS1 conserved druggable pockets - amenable to pharmacological modulation; NS1 mutations Y171A, K175A (CDP1), W102A (CDP3), Q121A and G184P (Multi-CDPs) impaired A(H1N1)pdm09 virus replication, in vitro; The new NS1 hot spots: NS1–K175, -W102, and -Q121 were characterized for the first time, using the A(H1N1)pdm09 virus; This map-and-mutate antiviral rationale can be promptly applied to other proteins of (re)emergent viruses.

Keywords

Influenza Influenza A Vrus Antiviral Strategy Antiviral Target Druggable Pockets NS1 Viral Replication Infecções Respiratórias Resistência aos Antimicrobianos