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Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against NaV.
- Source :
-
Science (New York, N.Y.) [Science] 2016 Nov 18; Vol. 354 (6314), pp. 865-869. - Publication Year :
- 2016
-
Abstract
- The steroidal neurotoxin (-)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (Na <subscript>V</subscript> s). Here we report concise asymmetric syntheses of the natural (-) and non-natural (+) antipodes of batrachotoxin, as well both enantiomers of a C-20 benzoate-modified derivative. Electrophysiological characterization of these molecules against Na <subscript>V</subscript> subtypes establishes the non-natural toxin enantiomer as a reversible antagonist of channel function, markedly different in activity from (-)-batrachotoxin. Protein mutagenesis experiments implicate a shared binding side for the enantiomers in the inner pore cavity of Na <subscript>V</subscript> These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate Na <subscript>V</subscript> dynamics.<br /> (Copyright © 2016, American Association for the Advancement of Science.)
- Subjects :
- Animals
Binding Sites
Muscle Proteins chemistry
Muscle Proteins genetics
Point Mutation
Protein Structure, Secondary
Rats
Sodium Channels chemistry
Sodium Channels genetics
Voltage-Gated Sodium Channel Blockers chemistry
Batrachotoxins chemical synthesis
Batrachotoxins pharmacology
Muscle Proteins antagonists & inhibitors
Voltage-Gated Sodium Channel Blockers chemical synthesis
Voltage-Gated Sodium Channel Blockers pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 354
- Issue :
- 6314
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 27856903
- Full Text :
- https://doi.org/10.1126/science.aag2981