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Design of bioactive peptides from naturally occurring μ-conotoxin structures.
Stevens M
,
Peigneur S
,
Dyubankova N
,
Lescrinier E
,
Herdewijn P
,
Tytgat J
.
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To date, cone snail toxins ("conotoxins") are of great interest in the pursuit of novel subtype-selective modulators of voltage-gated sodium channels (Na(v)s). Na(v)s participate in a wide range of electrophysiological processes. Consequently, their malfunctioning has been associated with numerous diseases. The development of subtype-selective modulators of Na(v)s remains highly important in the treatment of such disorders. In current research, a series of novel, synthetic, and bioactive compounds were designed based on two naturally occurring μ-conotoxins that target Na(v)s. The initial designed peptide contains solely 13 amino acids and was therefore named "Mini peptide." It was derived from the μ-conotoxins KIIIA and BuIIIC. Based on this Mini peptide, 10 analogues were subsequently developed, comprising 12-16 amino acids with two disulfide bridges. Following appropriate folding and mass verification, blocking effects on Na(v)s were investigated. The most promising compound established an IC(50) of 34.1 ± 0.01 nM (R2-Midi on Na(v)1.2). An NMR structure of one of our most promising compounds was determined. Surprisingly, this structure does not reveal an α-helix. We prove that it is possible to design small peptides based on known pharmacophores of μ-conotoxins without losing their potency and selectivity. These data can provide crucial material for further development of conotoxin-based therapeutics.
Buczek,
Structure and sodium channel activity of an excitatory I1-superfamily conotoxin.
2007, Pubmed,
Xenbase
Buczek,
Structure and sodium channel activity of an excitatory I1-superfamily conotoxin.
2007,
Pubmed
,
Xenbase
Bulaj,
Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels.
2005,
Pubmed
Campuzano,
Genetics and cardiac channelopathies.
2010,
Pubmed
Chang,
Predominant interactions between mu-conotoxin Arg-13 and the skeletal muscle Na+ channel localized by mutant cycle analysis.
1998,
Pubmed
,
Xenbase
Chen,
Binding modes of μ-conotoxin to the bacterial sodium channel (NaVAb).
2012,
Pubmed
Choudhary,
Docking of mu-conotoxin GIIIA in the sodium channel outer vestibule.
2007,
Pubmed
,
Xenbase
Clark,
Cyclization of conotoxins to improve their biopharmaceutical properties.
2012,
Pubmed
Cruz,
Conus geographus toxins that discriminate between neuronal and muscle sodium channels.
1985,
Pubmed
Dudley,
A mu-conotoxin-insensitive Na+ channel mutant: possible localization of a binding site at the outer vestibule.
1995,
Pubmed
Ekberg,
Conotoxin modulation of voltage-gated sodium channels.
2008,
Pubmed
Escayg,
Sodium channel SCN1A and epilepsy: mutations and mechanisms.
2010,
Pubmed
Favreau,
A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors.
2012,
Pubmed
,
Xenbase
French,
The tetrodotoxin receptor of voltage-gated sodium channels--perspectives from interactions with micro-conotoxins.
2010,
Pubmed
Fuller,
Oxidative folding of conotoxins sharing an identical disulfide bridging framework.
2005,
Pubmed
Han,
Structurally minimized mu-conotoxin analogues as sodium channel blockers: implications for designing conopeptide-based therapeutics.
2009,
Pubmed
,
Xenbase
Holford,
Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus.
2009,
Pubmed
,
Xenbase
Hui,
Electrostatic and steric contributions to block of the skeletal muscle sodium channel by mu-conotoxin.
2002,
Pubmed
Jurkat-Rott,
Sodium channelopathies of skeletal muscle result from gain or loss of function.
2010,
Pubmed
Khoo,
Lactam-stabilized helical analogues of the analgesic μ-conotoxin KIIIA.
2011,
Pubmed
,
Xenbase
Khoo,
Structure of the analgesic mu-conotoxin KIIIA and effects on the structure and function of disulfide deletion.
2009,
Pubmed
,
Xenbase
Leipold,
Molecular determinants for the subtype specificity of μ-conotoxin SIIIA targeting neuronal voltage-gated sodium channels.
2011,
Pubmed
Lewis,
Conus venom peptide pharmacology.
2012,
Pubmed
Lewis,
Isolation and structure-activity of mu-conotoxin TIIIA, a potent inhibitor of tetrodotoxin-sensitive voltage-gated sodium channels.
2007,
Pubmed
,
Xenbase
Li,
Clockwise domain arrangement of the sodium channel revealed by (mu)-conotoxin (GIIIA) docking orientation.
2001,
Pubmed
Linge,
Refinement of protein structures in explicit solvent.
2003,
Pubmed
Mantegazza,
Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders.
2010,
Pubmed
McArthur,
Orientation of μ-conotoxin PIIIA in a sodium channel vestibule, based on voltage dependence of its binding.
2011,
Pubmed
McArthur,
Multiple, distributed interactions of μ-conotoxin PIIIA associated with broad targeting among voltage-gated sodium channels.
2011,
Pubmed
McArthur,
Interactions of key charged residues contributing to selective block of neuronal sodium channels by μ-conotoxin KIIIA.
2011,
Pubmed
McIntosh,
A new family of conotoxins that blocks voltage-gated sodium channels.
1995,
Pubmed
Olivera,
Diversity of Conus neuropeptides.
1990,
Pubmed
Piotto,
Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions.
1992,
Pubmed
Schroeder,
Neuronally micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels.
2008,
Pubmed
,
Xenbase
Schwieters,
The Xplor-NIH NMR molecular structure determination package.
2003,
Pubmed
Shon,
Purification, characterization, synthesis, and cloning of the lockjaw peptide from Conus purpurascens venom.
1995,
Pubmed
Shon,
mu-Conotoxin PIIIA, a new peptide for discriminating among tetrodotoxin-sensitive Na channel subtypes.
1998,
Pubmed
Spence,
Characterization of the neurotoxic constituents of Conus geographus (L) venom.
1977,
Pubmed
Stein,
Torsion-angle molecular dynamics as a new efficient tool for NMR structure calculation.
1997,
Pubmed
Stephan,
The microI skeletal muscle sodium channel: mutation E403Q eliminates sensitivity to tetrodotoxin but not to mu-conotoxins GIIIA and GIIIB.
1994,
Pubmed
,
Xenbase
Stevens,
Neurotoxins and their binding areas on voltage-gated sodium channels.
2011,
Pubmed
Terlau,
Conus venoms: a rich source of novel ion channel-targeted peptides.
2004,
Pubmed
Tietze,
Structurally diverse μ-conotoxin PIIIA isomers block sodium channel NaV 1.4.
2012,
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
Walewska,
NMR-based mapping of disulfide bridges in cysteine-rich peptides: application to the mu-conotoxin SxIIIA.
2008,
Pubmed
West,
Mu-conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels in amphibian sympathetic and sensory neurons.
2002,
Pubmed
Zhang,
Cooccupancy of the outer vestibule of voltage-gated sodium channels by micro-conotoxin KIIIA and saxitoxin or tetrodotoxin.
2010,
Pubmed
,
Xenbase
Zhang,
Structural and functional diversities among mu-conotoxins targeting TTX-resistant sodium channels.
2006,
Pubmed
Zhang,
Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels.
2007,
Pubmed
,
Xenbase
Zuliani,
Sodium channel blockers as therapeutic target for treating epilepsy: recent updates.
2012,
Pubmed
