Discovery of selective, small-molecule inhibitors of RNA complexes--II. Self-splicing group I intron ribozyme.
Self-splicing group I intron RNA was chosen as a potential therapeutic target for small-molecule intervention. High-throughput screening methodologies have been developed to identify small organic molecules that regulate the activities of these catalytic introns. Group introns derived from pathogenic Pneumocystis carinii and phage T4 were used as model systems. Inhibitors identified from a library of approximately equal to 150,000 compounds were shown to regulate biochemical reactions including the two-step intron splicing and an RNA ligation catalyzed by the group I introns. These inhibitors provide a unique opportunity to understand small-molecule recognition of the self-splicing RNA. The methodologies developed for group I introns should be applicable to studies of other RNA systems.
Mei
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Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48106, USA.
Cui
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Lemrow
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Czarnik
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D017122:Bacteriophage T4 / Q000201:enzymology / Q000235:genetics; D001483:Base Sequence; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007438:Introns / Q000187:drug effects*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D011010:Pneumocystis / Q000201:enzymology / Q000235:genetics; D012313:RNA / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects*; D016337:RNA, Catalytic / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012331:RNA, Fungal / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D012322:RNA Precursors; D016337:RNA, Catalytic; D012331:RNA, Fungal; D012367:RNA, Viral; D012313:RNA