mu-Conotoxin KIIIA (mu-KIIIA) blocks mammalian voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. Previous structure-activity studies of mu-KIIIA identified a helical pharmacophore for VGSC blockade. This suggested a route for designing truncated analogues of mu-KIIIA by incorporating the key residues into an alpha-helical scaffold. As (i, i+4) lactam bridges constitute a proven approach for stabilizing alpha-helices, we designed and synthesized six truncated analogues of mu-KIIIA containing single lactam bridges at various locations. The helicity of these lactam analogues was analyzed by NMR spectroscopy, and their activities were tested against mammalian VGSC subtypes Na(v)1.1 through 1.7. Two of the analogues, Ac-cyclo9/13 [Asp9,Lys13]KIIIA7-14 and Ac-cyclo9/13 [Lys9,Asp13]KIIIA7-14, displayed mu M activity against VGSC subtypes Na(v)1.2 and Na(v)1.6; importantly, the subtype selectivity profile for these peptides matched that of mu-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.