Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors.

Abstract

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. I and comp. II) were designed, synthesized, and evaluated for anti-influenza virus activity. In the cytopathic effect (CPE) inhibition assay, comp. I and comp. II showed IC50 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 KD values of 1.398 and 1.670 μM, respectively. In vitro metabolic stability assays showed that comp. I and comp. II exhibited good stability to liver microsomes and considerably less sensitivity to aldehyde oxidase compared to pimodivir. The binding modes of comp. I and comp. II were similar to those of VX-787; however, comp. I and comp. II 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.

• Authors: Xinhong Li, Yijie Xu, Wei Li, Jinjing Che, Xu Zhao, Ruyuan Cao, Xingzhou Li, Song Li
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 28 Issue 4 (Feb 15 2023) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 36838837 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents

Topics

• Humans
• Molecular Dynamics Simulation
• Antiviral Agents (pharmacology)
• Influenza A Virus, H1N1 Subtype
• Influenza A Virus, H3N2 Subtype
• Influenza, Human (drug therapy)