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Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors.

ABSTRACT: 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.

SUBMITTER: Soret J 

PROVIDER: S-EPMC1150812 | biostudies-other | 2005 Jun

REPOSITORIES: biostudies-other

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Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors.

Soret Johann J   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  

Proceedings of the National Academy of Sciences of the United States of America 20050606 24

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 enha  ...[more]