Kinase inhibitor roscovitine as a PB2 cap-binding inhibitor against influenza a virus replication

Qi Huang; Yingyuan Zhong; Jingyan Li; Yilu Ye; Wenjiao Wu; Lizhu Chen; Mingkai Feng; Jie Yang; Shuwen Liu

doi:10.1016/j.bbrc.2020.04.034

Kinase inhibitor roscovitine as a PB2 cap-binding inhibitor against influenza a virus replication

Biochem Biophys Res Commun. 2020 Jun 11;526(4):1143-1149. doi: 10.1016/j.bbrc.2020.04.034. Epub 2020 Apr 13.

Authors

Qi Huang¹, Yingyuan Zhong¹, Jingyan Li¹, Yilu Ye¹, Wenjiao Wu¹, Lizhu Chen¹, Mingkai Feng¹, Jie Yang¹, Shuwen Liu²

Affiliations

¹ Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China.
² Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou, 510515, China. Electronic address: liusw@smu.edu.cn.

Abstract

In this study, we examined the impact of roscovitine, a cyclin-dependent kinase inhibitor (CDKI) that has entered phase I and II clinical trials, on influenza A viruses (IAVs) and its antiviral mechanism. The results illustrated that roscovitine inhibited multiple subtypes of influenza strains dose-dependently, including A/WSN/1933(H1N1), A/Aichi/2/68 (H3N2) and A/FM1/47 (H1N1) with IC₅₀ value of 3.35 ± 0.39, 7.01 ± 1.84 and 5.99 ± 1.89 μM, respectively. Moreover, roscovitine suppressed the gene transcription and genome replication steps in the viral life cycle. Further mechanistic studies indicated that roscovitine reduced viral polymerase activity and bound specifically to the viral PB2cap protein by fluorescence polarization assay (FP) and surface plasmon resonance (SPR). Therefore, we believed roscovitine, as a PB2cap inhibitor, was a prospective antiviral agent to be developed as therapeutic treatment against influenza A virus infection.

Keywords: Influenza a virus; Kinases inhibitor; PB2cap-binding inhibitor; Roscovitine; Viral polymerase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology*
DNA-Directed RNA Polymerases / metabolism
Dogs
Genome, Viral
Humans
Influenza A virus / drug effects
Influenza A virus / genetics
Influenza A virus / physiology*
Madin Darby Canine Kidney Cells
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
RNA Cap-Binding Proteins / metabolism*
RNA-Dependent RNA Polymerase / metabolism*
Roscovitine / chemistry
Roscovitine / pharmacology*
Transcription, Genetic / drug effects
Viral Proteins / metabolism*
Virus Internalization / drug effects
Virus Replication / drug effects*
Virus Replication / genetics

Substances

Antiviral Agents
PB2 protein, Influenzavirus A
Protein Kinase Inhibitors
RNA Cap-Binding Proteins
Viral Proteins
Roscovitine
RNA-Dependent RNA Polymerase
DNA-Directed RNA Polymerases