Small molecule peptidomimetic inhibitors of importin α/β mediated nuclear transport.
Nucleocytoplasmic transport of macromolecules is a fundamental process of eukaryotic cells. Translocation of proteins and many RNAs between the nucleus and cytoplasm is carried out by shuttling receptors of the β-karyopherin family, also called importins and exportins. Leptomycin B, a small molecule inhibitor of the exportin CRM1, has proved to be an invaluable tool for cell biologists, but up to now no small molecule inhibitors of nuclear import have been described. We devised a microtiter plate based permeabilized cell screen for small molecule inhibitors of the importin α/β pathway. By analyzing peptidomimetic libraries, we identified β-turn and α-helix peptidomimetic compounds that selectively inhibit nuclear import by importin α/β but not by transportin. Structure-activity relationship analysis showed that large aromatic residues and/or a histidine side chain are required for effective import inhibition by these compounds. Our validated inhibitors can be useful for in vitro studies of nuclear import, and can also provide a framework for synthesis of higher potency nuclear import inhibitors.
Ambrus
Géza
G
Department of Cell Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd., La Jolla, CA 92037, USA.
Whitby
Landon R
LR
Singer
Eric L
EL
Trott
Oleg
O
Choi
Euna
E
Olson
Arthur J
AJ
Boger
Dale L
DL
Gerace
Larry
L
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003198:Computer Simulation; D006224:Cricetinae; D006801:Humans; D051379:Mice; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D028901:alpha Karyopherins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D028961:beta Karyopherins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D057786:Peptidomimetics; D028901:alpha Karyopherins; D028961:beta Karyopherins