【博士論文】学術データベース

博士論文 / Identification of small molecule inhibitors for influenza a virus using in silico and in vitro approaches インシリコ及びインビトロスクリーニングによるA型インフルエンザウイルスの増殖阻害活性をもつ低分子化合物の同定

著者

書誌事項

タイトル

Identification of small molecule inhibitors for influenza a virus using in silico and in vitro approaches

タイトル別名

インシリコ及びインビトロスクリーニングによるA型インフルエンザウイルスの増殖阻害活性をもつ低分子化合物の同定

著者名

MAKAU JULIANN NZEMBI

学位授与大学

Nagasaki University (長崎大学) (大学ID:0073) (CAT機関ID:KI000877)

取得学位

博士(医学)

学位授与番号

甲医歯薬第997号

学位授与年月日

2017-09-20

注記・抄録

Influenza viruses have acquired resistance to approved neuraminidase-targeting drugs, increasing the need for new drug targets for the development of novel anti-influenza drugs. Nucleoprotein (NP) is an attractive target since it has an indispensable role in virus replication and its amino acid sequence is well conserved. In this study, we aimed to identify new inhibitors of the NP using a structure-based drug discovery algorithm, named Nagasaki University Docking Engine (NUDE), which has been established especially for the Destination for GPU Intensive Machine (DEGIMA) supercomputer. The hit compounds that showed high binding scores during in silico screening were subsequently evaluated for anti-influenza virus effects using a cell-based assay. A 4-hydroxyquinolinone compound, designated as NUD-1, was found to inhibit the replication of influenza virus in cultured cells. Analysis of binding between NUD-1 and NP using surface plasmon resonance assay and fragment molecular orbital calculations confirmed that NUD-1 binds to NP and could interfere with NP-NP interactions essential for virus replication. Time-of-addition experiments showed that the compound inhibited the mid-stage of infection, corresponding to assembly of the NP and other viral proteins. Moreover, NUD-1 was also effective against various types of influenza A viruses including a clinical isolate of A(H1N1)pdm09 influenza with a 50% inhibitory concentration range of 1.8–2.1 μM. Our data demonstrate that the combined use of NUDE system followed by the cell-based assay is useful to obtain lead compounds for the development of novel anti-influenza drugs.

開始ページ : e0173582

元資料の権利情報 : © 2017 Makau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

各種コード

NII論文ID(NAID)

500001045257

NII著者ID(NRID)
  • 8000001148091
DOI (出版社)

10.1371/journal.pone.0173582

DOI

info:doi/10.1371/journal.pone.0173582

本文言語コード

eng

データ提供元

機関リポジトリ / NDLデジタルコレクション

外部リンク

DOI

博士論文 / 長崎大学 / 医学

博士論文 / 長崎大学

博士論文 / 医学

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