Cargando…

Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir

Pimodivir exerts an antiviral effect on the early stages of influenza A virus replication by inhibiting the cap-binding function of polymerase basic protein 2 (PB2). In this study, we used a combination of sequence analysis and phenotypic methods to evaluate pimodivir susceptibility of influenza A v...

Descripción completa

Detalles Bibliográficos
Autores principales: Patel, Mira C., Chesnokov, Anton, Jones, Joyce, Mishin, Vasiliy P., De La Cruz, Juan A., Nguyen, Ha T., Zanders, Natosha, Wentworth, David E., Davis, Todd C., Gubareva, Larisa V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8978222/
https://www.ncbi.nlm.nih.gov/pubmed/33581212
http://dx.doi.org/10.1016/j.antiviral.2021.105035
_version_ 1784680929431650304
author Patel, Mira C.
Chesnokov, Anton
Jones, Joyce
Mishin, Vasiliy P.
De La Cruz, Juan A.
Nguyen, Ha T.
Zanders, Natosha
Wentworth, David E.
Davis, Todd C.
Gubareva, Larisa V.
author_facet Patel, Mira C.
Chesnokov, Anton
Jones, Joyce
Mishin, Vasiliy P.
De La Cruz, Juan A.
Nguyen, Ha T.
Zanders, Natosha
Wentworth, David E.
Davis, Todd C.
Gubareva, Larisa V.
author_sort Patel, Mira C.
collection PubMed
description Pimodivir exerts an antiviral effect on the early stages of influenza A virus replication by inhibiting the cap-binding function of polymerase basic protein 2 (PB2). In this study, we used a combination of sequence analysis and phenotypic methods to evaluate pimodivir susceptibility of influenza A viruses collected from humans and other hosts. Screening PB2 sequences for substitutions previously associated with reduced pimodivir susceptibility revealed a very low frequency among seasonal viruses circulating in the U.S. during 2015–2020 (<0.03%; 3/11,934) and among non-seasonal viruses collected in various countries during the same period (0.2%; 18/8971). Pimodivir potently inhibited virus replication in two assays, a single-cycle HINT and a multi-cycle FRA, with IC(50) values in a nanomolar range. Median IC(50) values determined by HINT were similar for both subtypes of seasonal viruses, A(H1N1)pdm09 and A(H3N2), across three seasons. Human seasonal viruses with PB2 substitutions S324C, S324R, or N510K displayed a 27–317-fold reduced pimodivir susceptibility by HINT. In addition, pimodivir was effective at inhibiting replication of a diverse group of animal-origin viruses that have pandemic potential, including avian viruses of A(H5N6) and A(H7N9) subtypes. A rare PB2 substitution H357N was identified in an A(H4N2) subtype poultry virus that displayed >100-fold reduced pimodivir susceptibility. Our findings demonstrate a broad inhibitory activity of pimodivir and expand the existing knowledge of amino acid substitutions that can reduce susceptibility to this investigational antiviral.
format Online
Article
Text
id pubmed-8978222
institution National Center for Biotechnology Information
language English
publishDate 2021
record_format MEDLINE/PubMed
spelling pubmed-89782222022-04-04 Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir Patel, Mira C. Chesnokov, Anton Jones, Joyce Mishin, Vasiliy P. De La Cruz, Juan A. Nguyen, Ha T. Zanders, Natosha Wentworth, David E. Davis, Todd C. Gubareva, Larisa V. Antiviral Res Article Pimodivir exerts an antiviral effect on the early stages of influenza A virus replication by inhibiting the cap-binding function of polymerase basic protein 2 (PB2). In this study, we used a combination of sequence analysis and phenotypic methods to evaluate pimodivir susceptibility of influenza A viruses collected from humans and other hosts. Screening PB2 sequences for substitutions previously associated with reduced pimodivir susceptibility revealed a very low frequency among seasonal viruses circulating in the U.S. during 2015–2020 (<0.03%; 3/11,934) and among non-seasonal viruses collected in various countries during the same period (0.2%; 18/8971). Pimodivir potently inhibited virus replication in two assays, a single-cycle HINT and a multi-cycle FRA, with IC(50) values in a nanomolar range. Median IC(50) values determined by HINT were similar for both subtypes of seasonal viruses, A(H1N1)pdm09 and A(H3N2), across three seasons. Human seasonal viruses with PB2 substitutions S324C, S324R, or N510K displayed a 27–317-fold reduced pimodivir susceptibility by HINT. In addition, pimodivir was effective at inhibiting replication of a diverse group of animal-origin viruses that have pandemic potential, including avian viruses of A(H5N6) and A(H7N9) subtypes. A rare PB2 substitution H357N was identified in an A(H4N2) subtype poultry virus that displayed >100-fold reduced pimodivir susceptibility. Our findings demonstrate a broad inhibitory activity of pimodivir and expand the existing knowledge of amino acid substitutions that can reduce susceptibility to this investigational antiviral. 2021-04 2021-02-10 /pmc/articles/PMC8978222/ /pubmed/33581212 http://dx.doi.org/10.1016/j.antiviral.2021.105035 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Patel, Mira C.
Chesnokov, Anton
Jones, Joyce
Mishin, Vasiliy P.
De La Cruz, Juan A.
Nguyen, Ha T.
Zanders, Natosha
Wentworth, David E.
Davis, Todd C.
Gubareva, Larisa V.
Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir
title Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir
title_full Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir
title_fullStr Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir
title_full_unstemmed Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir
title_short Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir
title_sort susceptibility of widely diverse influenza a viruses to pb2 polymerase inhibitor pimodivir
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8978222/
https://www.ncbi.nlm.nih.gov/pubmed/33581212
http://dx.doi.org/10.1016/j.antiviral.2021.105035
work_keys_str_mv AT patelmirac susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir
AT chesnokovanton susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir
AT jonesjoyce susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir
AT mishinvasiliyp susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir
AT delacruzjuana susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir
AT nguyenhat susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir
AT zandersnatosha susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir
AT wentworthdavide susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir
AT davistoddc susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir
AT gubarevalarisav susceptibilityofwidelydiverseinfluenzaavirusestopb2polymeraseinhibitorpimodivir