Leptomycin

Leptomycin refers to a group of secondary metabolites produced by Streptomyces species, with leptomycin B (LMB) being the best known member. These are polyketide macrolides that act as potent inhibitors of CRM1/XPO1-mediated nuclear export.

Mechanism of action is based on covalent modification of the export receptor CRM1. Leptomycin B contains an electrophilic functional group capable of forming a covalent bond with a cysteine residue in CRM1 in the presence of RanGTP. This reaction disrupts the interaction between CRM1 and cargo proteins containing leucine-rich nuclear export signals, blocking the export of these proteins from the nucleus to the cytoplasm. As a result, NES-bearing proteins accumulate in the nucleus, altering the localization and function of numerous cellular factors.

Biological and research applications center on its use as a molecular tool to study nuclear-cytoplasmic transport. By inhibiting CRM1, leptomycin B helps identify NES-containing cargo, characterize export pathways, and analyze the subcellular distribution of transcription factors and other regulators. Its effects on cell cycle progression and stress responses have also been explored in various systems. Due to its high potency and broad impact on cellular physiology, leptomycin B is used exclusively as a laboratory reagent.

Safety and regulatory status reflect that leptomycin B is not approved for clinical use. Its toxicity and unfavorable pharmacokinetic properties limit potential therapeutic applications, and handling is restricted to controlled research settings with appropriate safety measures.

Related compounds include leptomycin A and other analogs, which share the general mechanism of CRM1 blockade but differ in potency and pharmacological properties.