Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors.
The prevalence of alternative splicing as a target for alterations leading to human genetic disorders makes it highly relevant for therapy. Here we have used in vitro splicing reactions with different splicing reporter constructs to screen 4,000 chemical compounds for their ability to selectively inhibit spliceosome assembly and splicing. We discovered indole derivatives as potent inhibitors of the splicing reaction. Importantly, compounds of this family specifically inhibit exonic splicing enhancer (ESE)-dependent splicing, because they interact directly and selectively with members of the serine-arginine-rich protein family. Treatment of cells expressing reporter constructs with ESE sequences demonstrated that selected indole derivatives mediate inhibition of ESE usage in vivo and prevent early splicing events required for HIV replication. This discovery opens the exciting possibility of a causal pharmacological treatment of aberrant splicing in human genetic disorders and development of new antiviral therapeutic approaches.
Soret
Johann
J
Institut de Génétique Moléculaire de Montpellier, Unité Mixte de Recherche 5535, Centre National de Recherche Scientifique, 1919, Route de Mende, 34293 Montpellier, France.
Bakkour
Nadia
N
Maire
Sophie
S
Durand
Sébastien
S
Zekri
Latifa
L
Gabut
Mathieu
M
Fic
Weronika
W
Divita
Gilles
G
Rivalle
Christian
C
Dauzonne
Daniel
D
Nguyen
Chi Hung
CH
Jeanteur
Philippe
P
Tazi
Jamal
J
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D017931:DNA Primers; D005822:Genetic Vectors / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D012326:RNA Splicing / Q000187:drug effects / Q000502:physiology*; D012261:Ribonucleoproteins / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D013050:Spectrometry, Fluorescence; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D007211:Indoles; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors