Controlling Protein Transport by Small Molecules

Karl      Gademann

Abstract

Many proteins are transported from the nucleus to the cytoplasm by the exportin CRM1, which recognizes cargo proteins through a leucine rich nuclear export signal (NES). This nuclear export process can be inhibited by several small molecules, both natural products and fully synthetic compounds. The structural basis for the inhibition of nuclear export by leptomycin (LMB) based on disruption of the protein/protein interaction between CRM1 and cargo proteins is discussed. The chemistry and inhibition of nucleocytoplasmic transport of leptomycin, anguinomycin and derivatives, goniothalamin, JBIR-02, valtrate, dihydrovaltrate, ACA, peumusolide A and several synthetic compounds are presented. Consequences for the design of nuclear export inhibitors are discussed, and the potential of these compounds as anticancer agents is evaluated.

Keywords: Nuclear export, natural products, chemical biology, anticancer compounds, cell biology, biopolymers, chemical genetics, protein/protein interaction, chemical inteference, phenotypes