Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Med Chem
2011 Nov 10;5421:7558-66. doi: 10.1021/jm200839a.
Show Gene links
Show Anatomy links
Lactam-stabilized helical analogues of the analgesic μ-conotoxin KIIIA.
Khoo KK
,
Wilson MJ
,
Smith BJ
,
Zhang MM
,
Gulyas J
,
Yoshikami D
,
Rivier JE
,
Bulaj G
,
Norton RS
.
???displayArticle.abstract???
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 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 μM activity against VGSC subtypes Na(V)1.2 and Na(V)1.6; 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.
???displayArticle.pubmedLink???
21962108
???displayArticle.pmcLink???PMC3228837 ???displayArticle.link???J Med Chem ???displayArticle.grants???[+]
Bartels,
The program XEASY for computer-supported NMR spectral analysis of biological macromolecules.
1995, Pubmed
Bartels,
The program XEASY for computer-supported NMR spectral analysis of biological macromolecules.
1995,
Pubmed
Bulaj,
Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels.
2005,
Pubmed
Bussi,
Canonical sampling through velocity rescaling.
2007,
Pubmed
Cox,
An SCN9A channelopathy causes congenital inability to experience pain.
2006,
Pubmed
Cummins,
The roles of sodium channels in nociception: Implications for mechanisms of pain.
2007,
Pubmed
Fiser,
Modeller: generation and refinement of homology-based protein structure models.
2003,
Pubmed
Han,
Structurally minimized mu-conotoxin analogues as sodium channel blockers: implications for designing conopeptide-based therapeutics.
2009,
Pubmed
,
Xenbase
Houston,
Lactam bridge stabilization of alpha-helical peptides: ring size, orientation and positional effects.
1995,
Pubmed
Jorgensen,
The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin.
1988,
Pubmed
Khoo,
Structure of the analgesic mu-conotoxin KIIIA and effects on the structure and function of disulfide deletion.
2009,
Pubmed
,
Xenbase
Kirby,
Identification of high-potency neuropeptide Y analogues through systematic lactamization.
1997,
Pubmed
Lanigan,
Designed peptide analogues of the potassium channel blocker ShK toxin.
2001,
Pubmed
,
Xenbase
Li,
Minimization of a polypeptide hormone.
1995,
Pubmed
Marqusee,
Helix stabilization by Glu-...Lys+ salt bridges in short peptides of de novo design.
1987,
Pubmed
McArthur,
Interactions of key charged residues contributing to selective block of neuronal sodium channels by μ-conotoxin KIIIA.
2011,
Pubmed
Merutka,
'Random coil' 1H chemical shifts obtained as a function of temperature and trifluoroethanol concentration for the peptide series GGXGG.
1995,
Pubmed
Moellering,
Direct inhibition of the NOTCH transcription factor complex.
2009,
Pubmed
Momin,
Sensory neuron voltage-gated sodium channels as analgesic drug targets.
2008,
Pubmed
Norton,
Mu-conotoxins as leads in the development of new analgesics.
2010,
Pubmed
Norton,
Conotoxins down under.
2006,
Pubmed
Pardi,
Calibration of the angular dependence of the amide proton-C alpha proton coupling constants, 3JHN alpha, in a globular protein. Use of 3JHN alpha for identification of helical secondary structure.
1984,
Pubmed
Piotto,
Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions.
1992,
Pubmed
Shepherd,
Single turn peptide alpha helices with exceptional stability in water.
2005,
Pubmed
Siqueira,
Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia.
2009,
Pubmed
Taylor,
The synthesis and study of side-chain lactam-bridged peptides.
2002,
Pubmed
Terlau,
Conus venoms: a rich source of novel ion channel-targeted peptides.
2004,
Pubmed
Trivedi,
The role of thiols and disulfides on protein stability.
2009,
Pubmed
Van Der Haegen,
Importance of position 8 in μ-conotoxin KIIIA for voltage-gated sodium channel selectivity.
2011,
Pubmed
,
Xenbase
Weiss,
Loss-of-function mutations in sodium channel Nav1.7 cause anosmia.
2011,
Pubmed
Wilson,
μ-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve.
2011,
Pubmed
,
Xenbase
Wishart,
The chemical shift index: a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy.
1992,
Pubmed
Wishart,
Relationship between nuclear magnetic resonance chemical shift and protein secondary structure.
1991,
Pubmed
Yao,
Structure, dynamics, and selectivity of the sodium channel blocker mu-conotoxin SIIIA.
2008,
Pubmed
,
Xenbase
Yao,
Stabilization of the helical structure of Y2-selective analogues of neuropeptide Y by lactam bridges.
2002,
Pubmed
Zhang,
μ-conotoxin KIIIA derivatives with divergent affinities versus efficacies in blocking voltage-gated sodium channels.
2010,
Pubmed
,
Xenbase
Zhang,
Synergistic and antagonistic interactions between tetrodotoxin and mu-conotoxin in blocking voltage-gated sodium channels.
2009,
Pubmed
,
Xenbase
Zhang,
Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels.
2007,
Pubmed
,
Xenbase
