tetano
Editor, Senior Moderator
Antiviral Res. 2019 Feb 8. pii: S0166-3542(18)30487-X. doi: 10.1016/j.antiviral.2019.02.003. [Epub ahead of print]
[h=1]Novel influenza inhibitors designed to target PB1 interactions with host importin RanBP5.[/h] Mohl G[SUP]1[/SUP], Liddle N[SUP]2[/SUP], Nygaard J[SUP]3[/SUP], Dorius A[SUP]2[/SUP], Lyons N[SUP]3[/SUP], Hodek J[SUP]4[/SUP], Weber J[SUP]4[/SUP], Michaelis D[SUP]5[/SUP], Busath DD[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] In search of novel targets for influenza inhibitors, a site on PB1 was selected for its high conservation and probable interaction with a host protein, RanBP5, that is key to nuclear import of PB1, where it complexes with PB2, PA, and NP to transcribe viral RNA. Docking with libraries of drug-like compounds led to a selection of five candidates that bound tightly and with a pose likely to inhibit protein binding. These were purchased and tested in vitro, found to be active, and then one was synthetically expanded to explore the structure-activity relationship. The top candidates had a carboxylic acid converted to an ester and electron-withdrawing substituents added to a phenyl group in the original structure. Resistance was slow to develop, but cytotoxicity was moderately high. Nuclear localization of PB1 and in vitro polymerase activity were both strongly inhibited.
Copyright ? 2019. Published by Elsevier B.V.
[h=4]KEYWORDS:[/h] Antiviral; Nuclear localization; Polymerase inhibition; Virtual screening
PMID: 30742842 DOI: 10.1016/j.antiviral.2019.02.003
[h=1]Novel influenza inhibitors designed to target PB1 interactions with host importin RanBP5.[/h] Mohl G[SUP]1[/SUP], Liddle N[SUP]2[/SUP], Nygaard J[SUP]3[/SUP], Dorius A[SUP]2[/SUP], Lyons N[SUP]3[/SUP], Hodek J[SUP]4[/SUP], Weber J[SUP]4[/SUP], Michaelis D[SUP]5[/SUP], Busath DD[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] In search of novel targets for influenza inhibitors, a site on PB1 was selected for its high conservation and probable interaction with a host protein, RanBP5, that is key to nuclear import of PB1, where it complexes with PB2, PA, and NP to transcribe viral RNA. Docking with libraries of drug-like compounds led to a selection of five candidates that bound tightly and with a pose likely to inhibit protein binding. These were purchased and tested in vitro, found to be active, and then one was synthetically expanded to explore the structure-activity relationship. The top candidates had a carboxylic acid converted to an ester and electron-withdrawing substituents added to a phenyl group in the original structure. Resistance was slow to develop, but cytotoxicity was moderately high. Nuclear localization of PB1 and in vitro polymerase activity were both strongly inhibited.
Copyright ? 2019. Published by Elsevier B.V.
[h=4]KEYWORDS:[/h] Antiviral; Nuclear localization; Polymerase inhibition; Virtual screening
PMID: 30742842 DOI: 10.1016/j.antiviral.2019.02.003