Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors
The PB2 subunit of the influenza RNA-dependent RNA polymerase (RdRp) has been identified as a promising target for the treatment of influenza. To expand the chemical space of the known influenza polymerase PB2 inhibitor–pimodivir (formerly VX-787) and improve its pharmacokinetic profile, two pimodiv...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/4/1849 |
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| author | Xinhong Li Yijie Xu Wei Li Jinjing Che Xu Zhao Ruyuan Cao Xingzhou Li Song Li |
| author_facet | Xinhong Li Yijie Xu Wei Li Jinjing Che Xu Zhao Ruyuan Cao Xingzhou Li Song Li |
| author_sort | Xinhong Li |
| collection | DOAJ |
| description | The PB2 subunit of the influenza RNA-dependent RNA polymerase (RdRp) has been identified as a promising target for the treatment of influenza. To expand the chemical space of the known influenza polymerase PB2 inhibitor–pimodivir (formerly VX-787) and improve its pharmacokinetic profile, two pimodivir analogs containing 2,3-dihydro-imidazopyridine fragment (comp. <b>I</b> and comp. <b>II</b>) were designed, synthesized, and evaluated for anti-influenza virus activity. In the cytopathic effect (CPE) inhibition assay, comp. <b>I</b> and comp. <b>II</b> showed IC<sub>50</sub> values of 0.07 and 0.09 μM for A/Puerto Rico/8/34 (H1N1) and 0.04 and 0.07 μM for A/Hong Kong/8/68 (H3N2), respectively. Protein-binding affinity assay results showed a concentration-dependent association and dissociation pattern, with K<sub>D</sub> values of 1.398 and 1.670 μM, respectively. In vitro metabolic stability assays showed that comp. <b>I</b> and comp. <b>II</b> exhibited good stability to liver microsomes and considerably less sensitivity to aldehyde oxidase compared to pimodivir. The binding modes of comp. <b>I</b> and comp. <b>II</b> were similar to those of VX-787; however, comp. <b>I</b> and comp. <b>II</b> had lower structural adaptability to PB2 than VX-787. Our results provide helpful information regarding the structure–activity relationship for the design of novel PB2 inhibitors and a reference for the development of drugs containing 2,3-dihydro-imidazopyridine fragments. |
| first_indexed | 2024-03-11T08:21:16Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T08:21:16Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-bd1d0ff22f444f6093f3f5fe011cc35b2023-11-16T22:24:04ZengMDPI AGMolecules1420-30492023-02-01284184910.3390/molecules28041849Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 InhibitorsXinhong Li0Yijie Xu1Wei Li2Jinjing Che3Xu Zhao4Ruyuan Cao5Xingzhou Li6Song Li7National Engineering Research Center for the Emergency Strategic Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Strategic Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Strategic Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Strategic Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaDepartment of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, ChinaNational Engineering Research Center for the Emergency Strategic Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Strategic Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Strategic Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaThe PB2 subunit of the influenza RNA-dependent RNA polymerase (RdRp) has been identified as a promising target for the treatment of influenza. To expand the chemical space of the known influenza polymerase PB2 inhibitor–pimodivir (formerly VX-787) and improve its pharmacokinetic profile, two pimodivir analogs containing 2,3-dihydro-imidazopyridine fragment (comp. <b>I</b> and comp. <b>II</b>) were designed, synthesized, and evaluated for anti-influenza virus activity. In the cytopathic effect (CPE) inhibition assay, comp. <b>I</b> and comp. <b>II</b> showed IC<sub>50</sub> values of 0.07 and 0.09 μM for A/Puerto Rico/8/34 (H1N1) and 0.04 and 0.07 μM for A/Hong Kong/8/68 (H3N2), respectively. Protein-binding affinity assay results showed a concentration-dependent association and dissociation pattern, with K<sub>D</sub> values of 1.398 and 1.670 μM, respectively. In vitro metabolic stability assays showed that comp. <b>I</b> and comp. <b>II</b> exhibited good stability to liver microsomes and considerably less sensitivity to aldehyde oxidase compared to pimodivir. The binding modes of comp. <b>I</b> and comp. <b>II</b> were similar to those of VX-787; however, comp. <b>I</b> and comp. <b>II</b> had lower structural adaptability to PB2 than VX-787. Our results provide helpful information regarding the structure–activity relationship for the design of novel PB2 inhibitors and a reference for the development of drugs containing 2,3-dihydro-imidazopyridine fragments.https://www.mdpi.com/1420-3049/28/4/1849influenza virusantiviralPB2 inhibitors2,3-dihydro-imidazopyridinemolecular dynamicsMM/PBSA |
| spellingShingle | Xinhong Li Yijie Xu Wei Li Jinjing Che Xu Zhao Ruyuan Cao Xingzhou Li Song Li Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors Molecules influenza virus antiviral PB2 inhibitors 2,3-dihydro-imidazopyridine molecular dynamics MM/PBSA |
| title | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors |
| title_full | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors |
| title_fullStr | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors |
| title_full_unstemmed | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors |
| title_short | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors |
| title_sort | design synthesis biological evaluation and molecular dynamics simulation of influenza polymerase pb2 inhibitors |
| topic | influenza virus antiviral PB2 inhibitors 2,3-dihydro-imidazopyridine molecular dynamics MM/PBSA |
| url | https://www.mdpi.com/1420-3049/28/4/1849 |
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