Li X, Xu Y, Li W, Che J, Zhao X, Cao R, Li X, Li S. Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors. Molecules. 2023 Feb 15;28(4):1849
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.
See Also:
Latest articles in those days:
- Nucleic acid detection and genomic sequence analysis of one H5N1 avian influenza virus from wide birds around Qinghai Lake 1 days ago
- An aggregated dataset of serial morbidity and titer measurements from influenza A virus-infected ferrets 2 days ago
- Structures of H5N1 influenza polymerase with ANP32B reveal mechanisms of genome replication and host adaptation 4 days ago
- Risk assessment of a highly pathogenic H5N1 influenza virus from mink 4 days ago
- Detection of clade 2.3.4.4b highly pathogenic H5N1 influenza virus in New York City 4 days ago
[Go Top] [Close Window]