Disulfide-Depleted Selenoconopeptides: Simplified Oxidative Folding of Cysteine-Rich Peptides
journal contributionposted on 08.07.2010, 00:00 by Tiffany S. Han, Min-Min Zhang, Konkallu Hanumae Gowd, Aleksandra Walewska, Doju Yoshikami, Baldomero M. Olivera, Grzegorz Bulaj
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 μ-conopeptide KIIIA into a disulfide-depleted selenoconopeptide (by removal of a noncritical disulfide bridge and substitution of another disulfide bridge 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 analogues containing a single disulfide bridge allowed rapid positional scanning at Lys7 of μ-KIIIA, resulting in the identification of K7L as a mutation that improved the peptide’s selectivity in blocking a neuronal (Nav1.2) over a muscle (Nav1.4) 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.