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author:("Gulyas, josef")
1.  Lactam-stabilized helical analogues of the analgesic μ-conotoxin KIIIA 
Journal of medicinal chemistry  2011;54(21):7558-7566.
μ-Conotoxin KIIIA (μ-KIIIA) blocks mammalian voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. Previous structure-activity studies of μ-KIIIA identified a helical pharmacophore for VGSC blockade. This suggested a route for designing truncated analogues of μ-KIIIA by incorporating the key residues into an α-helical scaffold. As (i, i+4) lactam bridges constitute a proven approach for stabilizing α-helices, we designed and synthesized six truncated analogues of μ-KIIIA containing single lactam bridges at various locations. The helicity of these lactam analogues was analysed by NMR spectroscopy, and their activities were tested against mammalian VGSC subtypes NaV1.1 through 1.7. Two of the analogues, Ac-cyclo9/13[Asp9,Lys13]KIIIA7–14 and Ac-cyclo9/13[Lys9,Asp13]KIIIA7–14, displayed µM activity against VGSC subtypes NaV1.2 and NaV1.6; importantly, the subtype selectivity profile for these peptides matched that of μ-KIIIA. Our study highlights structure-activity relationships within these helical mimetics and provides a basis for the design of additional truncated peptides as potential analgesics.
doi:10.1021/jm200839a
PMCID: PMC3228837  PMID: 21962108

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