tetano
Editor, Senior Moderator
Antiviral Res. 2016 Aug 23. pii: S0166-3542(16)30206-6. doi: 10.1016/j.antiviral.2016.07.024. [Epub ahead of print]
[h=1]Antiviral activity of KR-23502 targeting nuclear export of influenza B virus ribonucleoproteins.[/h] Jang Y[SUP]1[/SUP], Lee HW[SUP]1[/SUP], Shin JS[SUP]1[/SUP], Go YY[SUP]1[/SUP], Kim C[SUP]1[/SUP], Shin D[SUP]1[/SUP], Malpani Y[SUP]2[/SUP], Han SB[SUP]2[/SUP], Jung YS[SUP]2[/SUP], Kim M[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
Copyright ? 2016. Published by Elsevier B.V.
[h=4]KEYWORDS:[/h] Antiviral effect; Influenza B virus; Matrix protein 1; Nuclear export protein; Spiro compound
PMID: 27565992 DOI: 10.1016/j.antiviral.2016.07.024
[PubMed - as supplied by publisher]
[h=1]Antiviral activity of KR-23502 targeting nuclear export of influenza B virus ribonucleoproteins.[/h] Jang Y[SUP]1[/SUP], Lee HW[SUP]1[/SUP], Shin JS[SUP]1[/SUP], Go YY[SUP]1[/SUP], Kim C[SUP]1[/SUP], Shin D[SUP]1[/SUP], Malpani Y[SUP]2[/SUP], Han SB[SUP]2[/SUP], Jung YS[SUP]2[/SUP], Kim M[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
Copyright ? 2016. Published by Elsevier B.V.
[h=4]KEYWORDS:[/h] Antiviral effect; Influenza B virus; Matrix protein 1; Nuclear export protein; Spiro compound
PMID: 27565992 DOI: 10.1016/j.antiviral.2016.07.024
[PubMed - as supplied by publisher]