Identification of influenza polymerase inhibitors targeting C-terminal domain of PA through surface plasmon resonance screening

Chun-Yeung Lo,Pang-Chui Shaw,Jacky Chi-Ki Ngo,David Chi-Cheong Wan,Guo Xin Wang,Wen-Ping Tang,Olive Tin-Wai Li,Leo Lit-Man Poon,Chun Hu

doi:10.1038/s41598-018-20772-9

Abstract

Currently, many strains of influenza A virus have developed resistance against anti-influenza drugs, and it is essential to find new chemicals to combat this virus. The influenza polymerase with three proteins, PA, PB1 and PB2, is a crucial component of the viral ribonucleoprotein (RNP) complex. Here, we report the identification of a hit compound 221 by surface plasmon resonance (SPR) direct binding screening on the C-terminal of PA (PAC). Compound 221 can subdue influenza RNP activities and attenuate influenza virus replication. Its analogs were subsequently investigated and twelve of them could attenuate RNP activities. One of the analogs, compound 312, impeded influenza A virus replication in Madin-Darby canine kidney cells with IC50 of 27.0 ± 16.8 μM. In vitro interaction assays showed that compound 312 bound directly to PAC with Kd of about 40 μM. Overall, the identification of novel PAC-targeting compounds provides new ground for drug design against influenza virus in the future.

Highlights

Influenza virus is a major threat to the health of the community
The influenza RNA-dependent RNA polymerase (RdRP), consisting PA, PB1 and PB2 subunits, is a component of the viral ribonucleoprotein (RNP) complex that is crucial for viral transcription and replication[6]
PA-PB1 interaction is necessary for the assembly of the RdRP complex, and it is involved in the nuclear import of both proteins[12]

Summary

Introduction

Influenza virus is a major threat to the health of the community. The annual deaths caused by seasonal influenza epidemics range from 250000 to 5000001. Two hit compounds (compound 221 and 283) were discovered to attenuate RNP activities and inhibit influenza virus. Compound 221 and 283 could impede influenza virus (A/WSN/33) replication in viral yield reduction assay, with IC50 30.58 ± 21.37 and 1.67 ± 1.27 μM respectively (Fig. 2d,e).

Results

Conclusion