tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A. 2019 May 10. pii: 201901214. doi: 10.1073/pnas.1901214116. [Epub ahead of print]
[h=1]Destabilization of the human RED-SMU1 splicing complex as a basis for host-directed antiinfluenza strategy.[/h] Ashraf U[SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Tengo L[SUP]4[/SUP], Le Corre L[SUP]5[/SUP], Fournier G[SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Busca P[SUP]5[/SUP], McCarthy AA[SUP]6[/SUP], Rameix-Welti MA[SUP]7,[/SUP][SUP]8[/SUP], Gravier-Pelletier C[SUP]5[/SUP], Ruigrok RWH[SUP]4[/SUP], Jacob Y[SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Vidalain PO[SUP]9[/SUP], Pietrancosta N[SUP]10[/SUP], Cr?pin T[SUP]11[/SUP], Naffakh N[SUP]12,[/SUP][SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] New therapeutic strategies targeting influenza are actively sought due to limitations in current drugs available. Host-directed therapy is an emerging concept to target host functions involved in pathogen life cycles and/or pathogenesis, rather than pathogen components themselves. From this perspective, we focused on an essential host partner of influenza viruses, the RED-SMU1 splicing complex. Here, we identified two synthetic molecules targeting an α-helix/groove interface essential for RED-SMU1 complex assembly. We solved the structure of the SMU1 N-terminal domain in complex with RED or bound to one of the molecules identified to disrupt this complex. We show that these compounds inhibiting RED-SMU1 interaction also decrease endogenous RED-SMU1 levels and inhibit viral mRNA splicing and viral multiplication, while preserving cell viability. Overall, our data demonstrate the potential of RED-SMU1 destabilizing molecules as an antiviral therapy that could be active against a wide range of influenza viruses and be less prone to drug resistance.
[h=4]KEYWORDS:[/h] RED-SMU1 splicing complex; host-directed antivirals; influenza virus; splicing; structure-based drug screening
[h=1]Destabilization of the human RED-SMU1 splicing complex as a basis for host-directed antiinfluenza strategy.[/h] Ashraf U[SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Tengo L[SUP]4[/SUP], Le Corre L[SUP]5[/SUP], Fournier G[SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Busca P[SUP]5[/SUP], McCarthy AA[SUP]6[/SUP], Rameix-Welti MA[SUP]7,[/SUP][SUP]8[/SUP], Gravier-Pelletier C[SUP]5[/SUP], Ruigrok RWH[SUP]4[/SUP], Jacob Y[SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Vidalain PO[SUP]9[/SUP], Pietrancosta N[SUP]10[/SUP], Cr?pin T[SUP]11[/SUP], Naffakh N[SUP]12,[/SUP][SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] New therapeutic strategies targeting influenza are actively sought due to limitations in current drugs available. Host-directed therapy is an emerging concept to target host functions involved in pathogen life cycles and/or pathogenesis, rather than pathogen components themselves. From this perspective, we focused on an essential host partner of influenza viruses, the RED-SMU1 splicing complex. Here, we identified two synthetic molecules targeting an α-helix/groove interface essential for RED-SMU1 complex assembly. We solved the structure of the SMU1 N-terminal domain in complex with RED or bound to one of the molecules identified to disrupt this complex. We show that these compounds inhibiting RED-SMU1 interaction also decrease endogenous RED-SMU1 levels and inhibit viral mRNA splicing and viral multiplication, while preserving cell viability. Overall, our data demonstrate the potential of RED-SMU1 destabilizing molecules as an antiviral therapy that could be active against a wide range of influenza viruses and be less prone to drug resistance.
[h=4]KEYWORDS:[/h] RED-SMU1 splicing complex; host-directed antivirals; influenza virus; splicing; structure-based drug screening