title: Antiviral activity of KR-23502 targeting nuclear export of influenza B virus ribonucleoproteins.
abstract: The spiro compound 5,6-dimethyl-3H,3'H-spiro(benzofuran-2,1'-isobenzofuran)-3,3'-dione (KR-23502) has antiviral activity against influenza A and more potently B viruses. The aim of this study is to elucidate its mechanism of action. Subcellular localization and time-course expression of influenza B viral proteins, nucleoprotein (NP) and matrix protein 1 (M1), showed that KR-23502 reduced their amounts within 5 h post-infection. Early steps of virus life cycle, including virus entry, nuclear localization of NP and viral RNA-dependent RNA replication, were not affected by KR-23502. Instead it interrupted a later event corresponding to nuclear export of NP and M1 proteins. Delivery of viral ribonucleoprotein (vRNP)-M1 complex has been known to be mediated by the viral nuclear export protein (NEP) through interaction with cellular chromosomal maintenance 1 (CRM1) protein. In this study, we experimentally demonstrated that the compound targets the nuclear export of vRNP. Moreover, a single mutation (aspartate to glycine) at amino acid position 54 in M1 [M1(D54G)] was detected after 18 passages in the presence of KR-23502 with a 2-fold increase in 50% effective concentration indicating that this compound has a relatively high genetic barrier to resistance. Interestingly, it was observed that proteasome-mediated degradation of M1(D54G) was attenuated by KR-23502. In conclusion, we suggest that KR-23502 shows its anti-influenza activity by downregulating NEP/CRM1-mediated nuclear export of influenza vRNP and M1. KR-23502 provides a core chemical skeleton for further structure-based design of novel antivirals against influenza viruses.
authors: Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
authors: Yejin
authors: Y
authors: Jang
authors: Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
authors: Hye Won
authors: HW
authors: Lee
authors: Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
authors: Jin Soo
authors: JS
authors: Shin
authors: Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
authors: Yun Young
authors: YY
authors: Go
authors: Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
authors: Chonsaeng
authors: C
authors: Kim
authors: Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
authors: Daeho
authors: D
authors: Shin
authors: Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
authors: Yashwardhan
authors: Y
authors: Malpani
authors: Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
authors: Soo Bong
authors: SB
authors: Han
authors: Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
authors: Young-Sik
authors: YS
authors: Jung
authors: Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea. Electronic address: mkim@krict.re.kr.
authors: Meehyein
authors: M
authors: Kim
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000998:Antiviral Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D009981:Influenza B virus / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D007251:Influenza, Human / Q000188:drug therapy; D009154:Mutation; D012367:RNA, Viral; D012261:Ribonucleoproteins / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D014763:Viral Matrix Proteins / Q000187:drug effects; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: C583784:5,6-dimethyl-3H,3'H-spiro(benzofuran-2,1'-isobenzofuran)-3,3'-dione; D000998:Antiviral Agents; D001572:Benzofurans; D012367:RNA, Viral; D012261:Ribonucleoproteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins
keywords: Antiviral effect; Influenza B virus; Matrix protein 1; Nuclear export protein; Spiro compound