Synthetic Analogues 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

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Drugs do not act solely by canonical ligand-receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. 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 analogues. 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 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure-activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT's membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. 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. ©

Original languageEnglish (US)
Pages (from-to)2733-2743
Number of pages11
JournalBiochemistry
Volume57
Issue number18
DOIs
StatePublished - May 8 2018

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Voltage-Gated Potassium Channels
Lipid bilayers
Snails
Lipid Bilayers
Dimers
Modulation
Membranes
Pharmaceutical Chemistry
Marine Toxins
Pharmaceutical Preparations
Ligands
Chemical modification
Structure-Activity Relationship
Scaffolds
Disulfides
Ether
Modulators
Assays
Membrane Proteins
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Synthetic Analogues 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. / Dockendorff, Chris; Gandhi, Disha M.; Kimball, Ian H.; Eum, Kenneth S.; Rusinova, Radda; Ingólfsson, Helgi I.; Kapoor, Ruchi; Peyear, Thasin; Dodge, Matthew W.; Martin, Stephen F.; Aldrich, Richard W.; Andersen, Olaf S.; Sack, Jon T.

In: Biochemistry, Vol. 57, No. 18, 08.05.2018, p. 2733-2743.

Research output: Contribution to journalArticle

Dockendorff, C, Gandhi, DM, Kimball, IH, Eum, KS, Rusinova, R, Ingólfsson, HI, Kapoor, R, Peyear, T, Dodge, MW, Martin, SF, Aldrich, RW, Andersen, OS & Sack, JT 2018, 'Synthetic Analogues 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', Biochemistry, vol. 57, no. 18, pp. 2733-2743. https://doi.org/10.1021/acs.biochem.8b00292
Dockendorff, Chris ; Gandhi, Disha M. ; Kimball, Ian H. ; Eum, Kenneth S. ; Rusinova, Radda ; Ingólfsson, Helgi I. ; Kapoor, Ruchi ; Peyear, Thasin ; Dodge, Matthew W. ; Martin, Stephen F. ; Aldrich, Richard W. ; Andersen, Olaf S. ; Sack, Jon T. / Synthetic Analogues 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. In: Biochemistry. 2018 ; Vol. 57, No. 18. pp. 2733-2743.
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AU - Dockendorff, Chris

AU - Gandhi, Disha M.

AU - Kimball, Ian H.

AU - Eum, Kenneth S.

AU - Rusinova, Radda

AU - Ingólfsson, Helgi I.

AU - Kapoor, Ruchi

AU - Peyear, Thasin

AU - Dodge, Matthew W.

AU - Martin, Stephen F.

AU - Aldrich, Richard W.

AU - Andersen, Olaf S.

AU - Sack, Jon T

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N2 - Drugs do not act solely by canonical ligand-receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. 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 analogues. 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 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure-activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT's membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. 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. ©

AB - Drugs do not act solely by canonical ligand-receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. 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 analogues. 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 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure-activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT's membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. 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. ©

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