Exploring new antiviral targets for influenza and COVID-19: Mapping promising hot spots in viral RNA polymerases

Figueiredo-Nunes, Inês; Trigueiro-Louro, João; Rebelo-de-Andrade, Helena

http://hdl.handle.net/10400.18/8587

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Authors

Figueiredo-Nunes, Inês

Trigueiro-Louro, João

Rebelo-de-Andrade, Helena

Abstract(s)

Influenza and COVID-19 are infectious respiratory diseases that represent a major concern to public health with social and economic impact worldwide, for which the available therapeutic options are not satisfactory. The RdRp has a central role in viral replication and thus represents a major target for the development of antiviral approaches. In this study, we focused on Influenza A virus PB1 polymerase protein and the betacoronaviruses nsp12 polymerase protein, considering their functional and structural similarities. We have performed conservation and druggability analysis to map conserved druggable regions, that may have functional or structural importance in these proteins. We disclosed the most promising and new targeting regions for the discovery of new potential polymerase inhibitors. Conserved druggable regions of putative interaction with favipiravir and molnupiravir were also mapped. We have also compared and integrated the current findings with previous research.

Highlights: IAV PB1 and beta-CoVs nsp12 RdRp proteins bear/have highly conserved regions; Fingers and palm subdomains of the RdRp proteins represent the most promising regions; Over 150 new top-ranked hot spots were identified for each protein; New conserved druggable pockets suitable for drug modulation were disclosed.

Keywords

SARS-CoV-2 COVID-19 Betacoronaviruses Consensus Druggable Pocket Conservation Score Druggability Score Influenza A Virus PB1 Protein Influenza nsp12 Protein Infecções Respiratórias Resistência aos Antimicrobianos