Discovery, Synthesis, and Structure–Activity Relationships of Conotoxins

Akondi, Kalyana Bharati; Muttenthaler, Markus; Dutertre, Sébastien; Kaas, Quentin; Craik, David J.; Lewis, Richard J.; Alewood, Paul F.

doi:10.1021/cr400401e

Cited by 260 publications

(356 citation statements)

References 347 publications

Supporting

Mentioning

354

Contrasting

Order By: Relevance

“…18,28,29 However, isolated short peptides (ca. <20 residues), even those with a propensity to adopt α-helical structure, generally remain conformationally ill-defined in solution.…”

Section: Development Of the Fold-and-staple Strategymentioning

confidence: 99%

“…For instance, cyclotides and defensins exploit N-to C-cyclization and/or regiospecific disulfide pairing to reduce susceptibility to enzymatic digestions. 15- 18 These strategies have been emulated in artificial peptide constructs. [19][20][21][22] While protease resistance has been mainly thought to arise from reduced structural flexibility due to covalent cyclization, hydrophobic interactions and salt bridges are increasingly thought to be important.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Interplay of Disulfide Bonds, α-Helicity, and Hydrophobic Interactions Leads to Ultrahigh Proteolytic Stability of Peptides

Chen

Yang

et al. 2015

Biomacromolecules

View full text Add to dashboard Cite

The contribution of noncovalent interactions to the stability of naturally occurring peptides and proteins has been generally acknowledged, though how these can be rationally manipulated to improve the proteolytic stability of synthetic peptides remains to be explored. In this study, a platform to enhance the proteolytic stability of peptides was developed by controllably dimerizing them into α-helical dimers, connected by two disulfide bonds. This platform not only directs peptides toward an α-helical conformation but permits control of the interfacial hydrophobic interactions between the peptides of the dimer. Using two model dimeric systems constructed from the N-terminal α-helix of RNase A and known inhibitors for the E3 ubiquitin ligase MDM2 (and its homologue MDMX), a deeper understanding into the interplay of disulfide bonds, α-helicity, and hydrophobic interactions on enhanced proteolytic stability was sought out. Results reveal that all three parameters play an important role on attaining ultrahigh proteolytic resistance, a concept that can be exploited for the development of future peptide therapeutics. The understanding gained through this study will enable this strategy to be tailored to new peptides because the proposed strategy displays substantial tolerance to sequence permutation. It thus appears promising for conveniently creating prodrugs composed entirely of the therapeutic peptide itself (i.e., in the form of a dimer).

show abstract

“…18,28,29 However, isolated short peptides (ca. <20 residues), even those with a propensity to adopt α-helical structure, generally remain conformationally ill-defined in solution.…”

Section: Development Of the Fold-and-staple Strategymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Interplay of Disulfide Bonds, α-Helicity, and Hydrophobic Interactions Leads to Ultrahigh Proteolytic Stability of Peptides

Chen

Yang

et al. 2015

Biomacromolecules

View full text Add to dashboard Cite

show abstract

“…In more recent years, only tiny amounts of natural products, e.g. bungarotoxins (contains a-and b-forms), conotoxins, dihydro-b-erythroidine, a-lobeline and methyllycaconitine have been found to be worked as the competitively neuronal nAChR antagonists (Huganir and Miles, 1989;Changeux et al, 1992;Quek et al, 2010;Green et al, 2013;Akondi et al, 2014;Tsetlin, 2015;Wan et al, 2015). Among them, methyllycaconitine has often been dismissed as the a7 nAChR subtype antagonist with the best selectivity and strongest competitiveness.…”

Section: Introductionmentioning

confidence: 99%

Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure–activity relationships studies

Peng

Ding

2015

European Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

“…Based on the number of cysteine (C) residues, the arrangement of the disulfide bonds (S-Ss) and the consensus signal sequences, CTxs are categorized into various super-families (A, B, C, D, E, I, M, O, P, S and T etc.) [1,2]. To date, more than 26 super-families have been identified [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…[1,2]. To date, more than 26 super-families have been identified [1,2]. Most of them potently and selectively target a wide variety of ion channels, including sodium (Na + )-, potassium (K + )-and calcium Ca 2+) -channels, as well as membrane receptors, including nicotinic acetylcholine receptor (nAChR), 5-hydroxytryptamine receptor (5-HT3R), N-methyl-D-aspartate receptor (NMDAR) and G-protein-coupled receptor (GPCR).…”

Section: Introductionmentioning

confidence: 99%

A novel 4/6-type alpha-conotoxin ViIA selectively inhibits nAchR α3β2 subtype

Liu²,

Ding³

et al. 2015

ABBS

View full text Add to dashboard Cite

Conotoxins (CTxs) are typically small peptides composed of 12-50 amino acid residues with 2-5 disulfide bridges. Most of them potently and selectively target a wide variety of ion channels and membrane receptors. They are highly valued as neuropharmacological probes and in pharmaceutical development. In this work, a novel α4/6-CTx named ViIA (RDCCSNPPCAHNNPDC-NH 2 ) was identified from a cDNA library of the venom ducts of Conus virgo (C. virgo). ViIA was then synthesized chemically and its disulfide connectivity was identified as 'C 1 -C 3 , C 2 -C 4 '. Its molecular targets were further assessed using two-electrode voltage clamping. The results indicated that ViIA selectively inhibited nicotinic acetylcholine receptor (nAChR) α3β2 subtype with an IC 50 of 845.5 nM, but did not target dorsal root ganglion sodium (Na + )-, potassium (K + )-or calcium (Ca 2+ )-ion channels.Further structure-activity relationship analysis demonstrated that Arg 1 and His 11 but not Asp 2 were the functional residues. To the best of our knowledge, ViIA is the first 4/6 α-CTx that selectively inhibits nAChR α3β2 subtype. This finding expands the knowledge of targets of α4/6-family CTxs.

show abstract

Discovery, Synthesis, and Structure–Activity Relationships of Conotoxins

Cited by 260 publications

References 347 publications

The Interplay of Disulfide Bonds, α-Helicity, and Hydrophobic Interactions Leads to Ultrahigh Proteolytic Stability of Peptides

The Interplay of Disulfide Bonds, α-Helicity, and Hydrophobic Interactions Leads to Ultrahigh Proteolytic Stability of Peptides

Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure–activity relationships studies

A novel 4/6-type alpha-conotoxin ViIA selectively inhibits nAchR α3β2 subtype

Contact Info

Product

Resources

About

Discovery, Synthesis, and Structure–Activity Relationships of Conotoxins

Cited by 260 publications

References 347 publications

The Interplay of Disulfide Bonds, α-Helicity, and Hydrophobic Interactions Leads to Ultrahigh Proteolytic Stability of Peptides

The Interplay of Disulfide Bonds, α-Helicity, and Hydrophobic Interactions Leads to Ultrahigh Proteolytic Stability of Peptides

Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure–activity relationships studies

A novel 4/6-type alpha-conotoxin ViIA selectively inhibits nAchR &alpha;3&beta;2 subtype

Contact Info

Product

Resources

About

A novel 4/6-type alpha-conotoxin ViIA selectively inhibits nAchR α3β2 subtype