Open AccessDisulfide-Depleted Selenoconopeptides: Simplified Oxidative Folding of Cysteine-Rich Peptides
Author(s) -
Tiffany Han,
Min Min Zhang,
Konkallu Hanumae Gowd,
Aleksandra Walewska,
Doju Yoshikami,
Baldomero M. Olivera,
Grzegorz Bułaj
Publication year - 2010
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml900017q
Subject(s) - oxidative folding , disulfide bond , cysteine , chemistry , folding (dsp implementation) , peptide , combinatorial chemistry , protein disulfide isomerase , thiol , biophysics , biochemistry , electrical engineering , enzyme , engineering , biology
Despite the therapeutic promise of disulfide-rich, peptidic natural products, their discovery and structure/function studies have been hampered by inefficient oxidative folding methods for their synthesis. Here we report that converting the three disulfide-bridged mu-conopeptide KIIIA into a disulfide-depleted selenoconopeptide (by removal of a noncritical disulfide bridge and substitution of a disulfide- with a diselenide-bridge) dramatically simplified its oxidative folding while preserving the peptide's ability to block voltage-gated sodium channels. The simplicity of synthesizing disulfide-depleted selenopeptide analogs containing a single disulfide bridge allowed rapid positional scanning at Lys7 of mu-KIIIA, resulting in the identification of K7L as a mutation that improved the peptide's selectivity in blocking a neuronal (Na(v)1.2) over a muscle (Na(v)1.4) subtype of sodium channel. The disulfide-depleted selenopeptide strategy offers regioselective folding compatible with high throughput chemical synthesis and on-resin oxidation methods, and thus shows great promise to accelerate the use of disulfide-rich peptides as research tools and drugs.