Structure-based drug discovery for combating influenza virus by targeting the PA\u2013PB1 interaction

Ken Watanabe,Tsuyoshi Hamada,Yoshimasa Tanaka,Daisuke Ishibashi,Jiro Yasuda,Satoshi Mizuta,Hiroki Otaki,Takeshi Ishikawa,Noriyuki Nishida,Takehiro Nakagaki,Shuzo Urata

doi:10.1038/s41598-017-10021-w

Abstract

Influenza virus infections are serious public health concerns throughout the world. The development of compounds with novel mechanisms of action is urgently required due to the emergence of viruses with resistance to the currently-approved anti-influenza viral drugs. We performed in silico screening using a structure-based drug discovery algorithm called Nagasaki University Docking Engine (NUDE), which is optimised for a GPU-based supercomputer (DEstination for Gpu Intensive MAchine; DEGIMA), by targeting influenza viral PA protein. The compounds selected by NUDE were tested for anti-influenza virus activity using a cell-based assay. The most potent compound, designated as PA-49, is a medium-sized quinolinone derivative bearing a tetrazole moiety, and it inhibited the replication of influenza virus A/WSN/33 at a half maximal inhibitory concentration of 0.47 μM. PA-49 has the ability to bind PA and its anti-influenza activity was promising against various influenza strains, including a clinical isolate of A(H1N1)pdm09 and type B viruses. The docking simulation suggested that PA-49 interrupts the PA–PB1 interface where important amino acids are mostly conserved in the virus strains tested, suggesting the strain independent utility. Because our NUDE/DEGIMA system is rapid and efficient, it may help effective drug discovery against the influenza virus and other emerging viruses.

Highlights

Influenza is caused by acute influenza virus infection
600,000 compounds in the chemical compound library were ranked based on the docking score obtained by the Nagasaki University Docking Engine (NUDE), and the top 136 compounds designated as PA-1 to PA-136 were selected as candidates of anti-influenza compounds
We evaluated the antiviral activity of PA-49 using a plaque inhibition assay, which is the gold standard method for evaluating antiviral activity[30], in order to determine whether plaque formation in Madin–Darby canine kidney (MDCK) cells was suppressed by PA-49 treatment

Summary

Introduction

Influenza is caused by acute influenza virus infection. Influenza pandemics occur due to antigenic shifts in the virus and they have caused significant morbidity and mortality in humans. The development of anti-influenza viral drugs with novel mechanism of action is needed. SBDD has been used widely for the development of antiviral drugs, such as the HIV-1 proteinase inhibitor, nelfinavir[22] and influenza viral NA inhibitor zanamivir[23]. To facilitate the identification of novel drugs, we recently developed the Nagasaki University Docking Engine (NUDE) which efficiently runs on the DEstination for Gpu Intensive MAchine (DEGIMA) supercomputer. Using this system, we have succeeded in development of anti-prion compounds[24] and anti-influenza virus compounds that target influenza viral NP25. We found that a quinolinone derivative bearing a tetrazole moiety effectively suppressed the replication of influenza viruses

Methods

Results

Conclusion