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Nuclear export factor chromosome region maintenance 1 (CRM1) is an attractive anticancer and antiviral drug target that spurred several research efforts to develop its inhibitor. Noncovalent CRM1 inhibitors are desirable, but none is reported to date. Here, we present the crystal structure of yeast CRM1 in complex with S109, a substructure of CBS9106 (under clinical test). Superimposition with the LFS-829 (another covalent CRM1 inhibitor) complex inspired the design of a noncovalent CRM1 inhibitor. Among nine synthesized compounds, noncovalent CRM1 inhibitor 1 (NCI-1) showed a high affinity to human and yeast CRM1 in the absence or presence of GST-bound Rasrelated nuclear protein (RanGTP). Unlike covalent inhibitors, the crystal structure showed that NCI-1 is bound in the "open" nuclear export signal (NES) groove of CRM1, simultaneously occupying two hydrophobic pockets. NCI-1 additionally inhibited the nuclear export and proliferation of cells harboring the human CRM1-C528S mutant. Our work opens up the avenue of noncovalent CRM1 inhibitor development toward a more potent, less toxic, and broad-spectrum anticancer/antiviral therapy.

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Botulinum neurotoxins (BoNT) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. BoNT/A is the most toxic protein known to man and has been classified by the Centers of Disease Control (CDC) as one of the six highest-risk threat agents for bioterrorism. Of particular concern is the apparent lack of clinical interventions that can reverse cellular intoxication. Efforts to uncover molecules that can act within an intoxicated cell so as to provide symptomatic relief to BoNT/A are paramount. Aminopyridines have shown clinical efficacy for multiple sclerosis treatment as well as BoNT/A intoxication; yet, aminopyridines for BoNT/A treatment has been abandoned because of blood brain barrier (BBB) penetration producing undesired neurotoxic side effects. Two aminopyridines, (5 and 11), exhibited inhibitory activity toward Shaker-IR voltagegated potassium (K V 1.x) channels with potencies similar to that of the previous "gold-standard", 3,4-diaminopyridine (3,4-DAP), including reversal of symptoms from BoNT-induced paralysis in phrenic nerve-hemidiaphragm preparations. Importantly, pharmacokinetic experiments revealed a lack of BBB penetration of 5, which is a significant advancement toward resolving the neurotoxicity issues associated with prolonged 3,4-DAP treatments. Finally, 5 was found to be as effective as 3,4-DAP in rescuing BoNT-poisoned mice in the mouse lethality assay, signifying an optimized balance between the undesired permeability across the BBB, and the required permeability across lipid cellular membranes. The results demonstrate that 5 is the most promising small molecule K + channel inhibitor discovered to date for the treatment of BoNT/A intoxication. KeywordsBotulinum Neurotoxin; aminopyridine; K + channel inhibitors * To whom correspondence should be addressed. Phone: (+1) 858-784-2516. Fax: (+1) 858-784-2595. kdjanda@scripps.edu. SUPPORTING INFORMATION AVAILABLE Synthetic and computational procedures, HPLC traces and 1 H/ 13 C NMR spectra of compounds 4-12; additional details for the biological evaluation of compounds 5 and 11. This material is available free of charge via the Internet at

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