Synthesis and biological characterisation of a series of iberiotoxin analogues.
We report here the synthesis of iberiotoxin (IbTX), a 37-amino acid peptide containing three disulfide bridges, and a series of mono-looped analogues. All syntheses were conducted using Fmoc chemistry. Synthesis of IbTX gave a product which was indistinguishable from a reference sample in both its physico-chemical properties and its biological activity. A series of three mono-looped analogues, in which four of the six cysteines were replaced by alanine, were synthesised to give [Ala7,13,28,33]-IbTX, [Ala13,17,33,35]-IbTX and [Ala7,17,28,35]-IbTX. Oxidation of the linear form of [Ala7,17,28,35]-IbTX to form the Cys13 to Cys33 disulfide bridge proceeded more slowly than that of the other two analogues. None of these analogues was biologically active, indicating that no single loop is the mediator of channel blocking activity.
Flinn
J P
JP
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Murphy
R
R
Johns
R B
RB
Kunze
W A
WA
Angus
J A
JA
D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D004558:Electric Stimulation; D006168:Guinea Pigs; D013058:Mass Spectrometry; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology; D010084:Oxidation-Reduction; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012604:Scorpion Venoms / Q000737:chemistry; D013329:Structure-Activity Relationship; D014118:Toxins, Biological / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004220:Disulfides; D010455:Peptides; D012604:Scorpion Venoms; D014118:Toxins, Biological; C064719:iberiotoxin; D004121:Dimethyl Sulfoxide