Lactam-stabilized helical analogues of the analgesic μ-Conotoxin KIIIA

Khoo, Keith K., Wilson, Michael J., Smith, Brian J., Zhang, Min-Min, Gulyas, Joszef, Yoshikami, Doju, Rivier, Jean E., Bulaj, Grzegorz and Norton, Raymond S. 2011, Lactam-stabilized helical analogues of the analgesic μ-Conotoxin KIIIA, Journal of medicinal chemistry, vol. 54, no. 21, pp. 7558-7566, doi: 10.1021/jm200839a.

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Title Lactam-stabilized helical analogues of the analgesic μ-Conotoxin KIIIA
Author(s) Khoo, Keith K.
Wilson, Michael J.
Smith, Brian J.
Zhang, Min-Min
Gulyas, Joszef
Yoshikami, Doju
Rivier, Jean E.
Bulaj, Grzegorz
Norton, Raymond S.
Journal name Journal of medicinal chemistry
Volume number 54
Issue number 21
Start page 7558
End page 7566
Total pages 9
Publisher American Chemical Society
Place of publication Oxford, Eng.
Publication date 2011
ISSN 1520-4804
Summary 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 analyzed 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.
Language eng
DOI 10.1021/jm200839a
Indigenous content off
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2011, ACS Publications
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Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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