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Structural and Thermodynamic Analysis of the Resistance Development to Pimodivir (VX-787), the Clinical Inhibitor of Cap Binding to PB2 Subunit of Influenza A Polymerase
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SYSNO ASEP 0541489 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Structural and Thermodynamic Analysis of the Resistance Development to Pimodivir (VX-787), the Clinical Inhibitor of Cap Binding to PB2 Subunit of Influenza A Polymerase Author(s) Gregor, Jiří (UOCHB-X)
Radilová, Kateřina (UOCHB-X) ORCID
Brynda, Jiří (UOCHB-X) RID, ORCID
Fanfrlík, Jindřich (UOCHB-X) RID, ORCID
Konvalinka, Jan (UOCHB-X) RID, ORCID
Kožíšek, Milan (UOCHB-X) RID, ORCIDArticle number 1007 Source Title Molecules. - : MDPI
Roč. 26, č. 4 (2021)Number of pages 13 s. Language eng - English Country CH - Switzerland Keywords influenza A polymerase ; antivirals ; pimodivir ; VX-787 ; resistance OECD category Biochemistry and molecular biology R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure e-INFRA CZ - 90140 - CESNET, zájmové sdružení právnických osob Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000624159600001 EID SCOPUS 85102604093 DOI 10.3390/molecules26041007 Annotation Influenza A virus (IAV) encodes a polymerase composed of three subunits: PA, with endonuclease activity, PB1 with polymerase activity and PB2 with host RNA five-prime cap binding site. Their cooperation and stepwise activation include a process called cap-snatching, which is a crucial step in the IAV life cycle. Reproduction of IAV can be blocked by disrupting the interaction between the PB2 domain and the five-prime cap. An inhibitor of this interaction called pimodivir (VX-787) recently entered the third phase of clinical trial, however, several mutations in PB2 that cause resistance to pimodivir were observed. First major mutation, F404Y, causing resistance was identified during preclinical testing, next the mutation M431I was identified in patients during the second phase of clinical trials. The mutation H357N was identified during testing of IAV strains at Centers for Disease Control and Prevention. We set out to provide a structural and thermodynamic analysis of the interactions between cap-binding domain of PB2 wild-type and PB2 variants bearing these mutations and pimodivir. Here we present four crystal structures of PB2-WT, PB2-F404Y, PB2-M431I and PB2-H357N in complex with pimodivir. We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2022 Electronic address https://doi.org/10.3390/molecules26041007
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