Modification of Arg-13 of mu-conotoxin GIIIA with piperidinyl-Arg analogs and their relation to the inhibition of sodium channels.
mu-Conotoxin GIIIA, a peptide toxin isolated from the marine snail Conus geographus, preferentially blocks skeletal muscle sodium channels in vertebrates. In this study, analogs of mu-conotoxin GIIIA in which essential Arg-13 was replaced with arginine analogs consisting of a piperidyl framework to regulate length and direction of the side chain were synthesized. Synthesized analogs exhibited similar CD and NMR spectra to that of GIIIA, suggesting a three-dimensional structure identical to that of the native toxin. The biological activities of piperidyl analogs were decreased or lost despite the small change in the side chain of Arg-13. The investigated structure-activity relationships in inhibiting electrically stimulated muscle contraction suggest that the guanidinium group at amino acid position 13 interacts best when spaced with three to four carbons and placed in a vertical direction from the peptide loop. Thus, the position of the guanidinium group at Arg-13 of GIIIA must be located in a certain range for its strong interaction with the channel protein.
Nakamura
M
M
Graduate School of Bioagricultural Sciences, Nagoya University, Japan.
Niwa
Y
Y
Ishida
Y
Y
Kohno
T
T
Sato
K
K
Oba
Y
Y
Nakamura
H
H
D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry*; D002942:Circular Dichroism; D020916:Conotoxins / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D019906:Nuclear Magnetic Resonance, Biomolecular; D010880:Piperidines / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers
D020916:Conotoxins; D010880:Piperidines; D026941:Sodium Channel Blockers; C046101:conotoxin GIII; C032727:piperidine; D001120:Arginine