TY - JOUR
T1 - Lactam-stabilized helical analogues of the analgesic mu-conotoxin KIIIA
AU - Khoo, Keith
AU - Wilson, Michael
AU - Smith, Brian
AU - Zhang, Min-Min
AU - Gulyas, Joszef
AU - Yoshikami, Doju
AU - Rivier, Jean
AU - Bulaj, Grzegorz
AU - Norton, Raymond
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
UR - http://pubs.acs.org.ezproxy.lib.monash.edu.au/doi/full/10.1021/jm200839a
U2 - 10.1021/jm200839a
DO - 10.1021/jm200839a
M3 - Article
VL - 54
SP - 7558
EP - 7566
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 21
ER -