Conotoxins containing nonnatural backbone spacers: cladistic-based design, chemical synthesis, and improved analgesic activity.
Disulfide-rich neurotoxins from venomous animals continue to provide compounds with therapeutic potential. Minimizing neurotoxins often results in removal of disulfide bridges or critical amino acids. To address this drug-design challenge, we explored the concept of disulfide-rich scaffolds consisting of isostere polymers and peptidic pharmacophores. Flexible spacers, such as amino-3-oxapentanoic or 6-aminohexanoic acids, were used to replace conformationally constrained parts of a three-disulfide-bridged conotoxin, SIIIA. The peptide-polymer hybrids, polytides, were designed based on cladistic identification of nonconserved loci in related peptides. After oxidative folding, the polytides appeared to be better inhibitors of sodium currents in dorsal root ganglia and sciatic nerves in mice. Moreover, the polytides appeared to be significantly more potent and longer-lasting analgesics in the inflammatory pain model in mice, when compared to SIIIA. The resulting polytides provide a promising strategy for transforming disulfide-rich peptides into therapeutics.
Green
Brad R
BR
Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.
Catlin
Philip
P
Zhang
Min-Min
MM
Fiedler
Brian
B
Bayudan
Wendi
W
Morrison
Alex
A
Norton
Raymond S
RS
Smith
Brian J
BJ
Yoshikami
Doju
D
Olivera
Baldomero M
BM
Bulaj
Grzegorz
G
D000595:Amino Acid Sequence; D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D020916:Conotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D020916:Conotoxins; D010455:Peptides; D026941:Sodium Channel Blockers