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.

Selenium Nanoparticles Control H1N1 Virus by Inhibiting Inflammatory Response and Cell Apoptosis

“…The drugs that have been used clinically to treat the M2 ion channel and neuraminic acid inhibitors have been used for many years unchanged. Still, the virus has been changing, and drug resistance has become common [35]. In this study, nanoparticles and selenium were combined to investigate whether selenium nanoparticles (SeNPs) could exert antiviral effects in mice.…”

Viral RNA capping: Mechanisms and antiviral therapy

“…Nowadays, there are three basic ways to implement inhibitors that target the viral RNA capping process: either by binding to functional domains in viral capping enzymes or by using capsnatching proteins to block enzyme activity, [118][119][120][121][122][123][124][125][126][127][128][129][130][131] disrupting cofactors that sustain the structural integrity of capping enzymes, 132,133,135,136 and targeting of crucial host factors exploited by the virus during specific capping stages. 61,134 The first category of inhibitors is predominantly identified through the screening of molecules obstructing binding interactions, [119][120][121] as well as exploring and designing analogs of the methyl donor or its demethylated products to obstruct the S-adenosyl-1-methionine (SAM)-binding site of viral 2′-O MTase.…”

“…61,134 The first category of inhibitors is predominantly identified through the screening of molecules obstructing binding interactions, [119][120][121] as well as exploring and designing analogs of the methyl donor or its demethylated products to obstruct the S-adenosyl-1-methionine (SAM)-binding site of viral 2′-O MTase. [122][123][124]126 Endonuclease activity blockers 118,137,138,140 and competitive binding inhibitors of the capbinding domain, [128][129][130][131]141 exert antiviral roles in viruses that utilize the cap-snatching mechanisms. The SARS-CoV-2 nsp10 protein stands as a pivotal cofactor for the methyltransferase activity of viral nsp16.…”

Zoonotic Potential of Avian Influenza Virus: Knowns and Unknowns

“…But resistance to NA inhibitors can be seen due to the mutations in the NA protein (Burnham et al 2014). Antiviral agents include a variety of substances that target different stages of viral replication, such as NP inhibitors (Correa-Padilla et al 2023), PB2 inhibitors (Li et al 2023), PA inhibitors (Govorkova et al 2022), and RNAdependent RNA polymerase inhibitors (Shiraki and Daikoku 2020) can be used as antiviral agents (Huang et al 2023).…”