Structure-based drug discovery for combating influenza virus by targeting the PA–PB1 interaction

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.

Antiviral Activity of Peanut (Arachis hypogaea L.) Skin Extract Against Human Influenza Viruses

“…We have established crystal violet (CV) assay, 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 oseltamivir showed good antiviral activity as expected, since oseltamivir inhibits the release of virus particles thereby suppressing the spread of infection. Sensitivity of oseltamivir drastically decreased when the virus was infected with high titer (Fig.…”

Human BST-2/tetherin inhibits Junin virus release from host cells and its inhibition is partially counteracted by viral nucleoprotein

“…A modified version of pC-Candid-NP with a FLAG tag at C-terminal (pC-Candid-NP-FLAG) was constructed using KOD Plus mutagenesis kit (TOYOBO, Osaka, Japan) using two primers (sense 5′-GACG ATGA CGAC AAGT AAGC AGTG GGAG AGAC GATTCTAG-3′ and antisense 5′-TTTG TAGT CACC ACCC AGTG CATA GGCT GCCT TCGGGAGG-3′). Vesicular stomatitis Indiana virus (VSV) was prepared as previously described [41].…”

Advances in structure-assisted antiviral discovery for animal viral diseases

“…In 2017, structure-based drug discovery studies were done by targeting the PAÀPB1 interaction. Many potent antiinfluenza drugs were reported with the help of in silico simulation studies (Watanabe et al, 2017).…”