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Synthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

submitted on 21.02.2018, 04:50 and posted on 21.02.2018, 15:37 by Chris Dockendorff, Disha M. Gandhi, Ian H. Kimball, Kenneth S. Eum, Radda Rusinova, Helgi I. Ingólfsson, Ruchi Kapoor, Thasin Peyear, Matthew W. Dodge, Stephen F. Martin, Richard W. Aldrich, Olaf S. Andersen, Jon T. Sack
Distinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogs. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogs and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported.


NIH R15 HL127636 (C.D.); NIH T32 099608 (I.H.K.); NIH R01 NS096317 (J.T.S.); NIH R01 GM021432 (O.S.A.)


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Marquette University



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No conflict of interest