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Review
. 2014 Jun 11;114(11):5815-47.
doi: 10.1021/cr400401e. Epub 2014 Apr 10.

Discovery, synthesis, and structure-activity relationships of conotoxins

Kalyana B Akondi  1 , Markus Muttenthaler, Sébastien Dutertre, Quentin Kaas, David J Craik, Richard J Lewis, Paul F Alewood
Affiliations
Review

Discovery, synthesis, and structure-activity relationships of conotoxins

Kalyana B Akondi et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1. Classification of conotoxins into various families and superfamilies.
Conotoxins are classified into various superfamilies based on their conserved signal sequence homology. Further classification into families is based on their disulfide bond framework and their target receptor. The target receptors for the conotoxin families, which do not have a specified receptor shown in this figure, are yet to be identified. NE-Norepinephrine; nAChR-nicotinic acetylcholine receptor.
Figure 2
Figure 2. Conotoxin nomenclature.
Conotoxin naming convention is based on the NC-IUPHAR system. The first letter in Greek indicates the conotoxin’s pharmacological target i.e. α-conotoxin targeting the nicotinic acetylcholine receptors. The next one or two uppercase letters represent the species from which it was isolated in this case, Conus Pennaceus. This is followed by a Roman numeral, I, providing information on the disulfide framework (e.g.: CC-C-C). Finally, an uppercase letter denotes the order of discovery of the conotoxin within that category. If the mechanism of action of the conotoxin is yet to be determined, the Greek letter is omitted, the species name is in lower case letters, an Arabic numeral is used to designate the disulfide bonding pattern, and a small letter is used to specify the peptide variant.
Figure 3
Figure 3. Distribution of mature conopeptide sequence lengths in the ConoServer dataset.
Figure 4
Figure 4
a: Most commonly discovered or studied conopeptide folds. All available three-dimensional structures in ConoServer corresponding to the four folds A to D were overlaid. The peptide backbone of each conopeptide is shown using a ribbon representation. The alpha carbon of cystine residues or equivalent (i.e. selenocysteines or half-carba-bridge) are represented as spheres, and the cross-links are shown using orange sticks. The most structurally conserved regions are highlighted in red or in orange. Some structures presenting interesting differences to the fold and discussed in the text are colored in green or blue. The half-cystines have been numbered according to their sequential position in the primary sequence, allowing to clearly distinguish the cross-link connectivities. A description of all the structures is provided in Table 4. This figure was partly drawn using PyMol. b: Conopeptide folds with only a few representatives. All available three-dimensional structures in ConoServer corresponding to the four folds E to L and Kunitz are overlaid. The peptide backbone structure of each conopeptide is shown using a ribbon representation, and also using a cartoon representation for fold G, K and Kunitz. The alpha carbons of the cystine residues are represented as spheres, and the cross-links are shown using orange sticks. The most structurally conserved regions are highlighted in red for the Kunitz fold. The half-cystines have been numbered according to their sequential position in the primary sequence to clearly distinguish the cross-link connectivities. A description of all the structures is provided in Table 4. The figure was partly drawn using PyMol.
Figure 5
Figure 5. Key steps involved in the assembly of peptides by solid phase peptide synthesis.
Peptides are assembled via successive rounds of Nα deprotection and addition of activated amino acid. In the final step the peptide is cleaved from the solid support with simultaneous removal of the side chain protecting groups.
Figure 6
Figure 6. Non-selective isomer formation in a two-disulfide bond containing peptide.
Figure 7
Figure 7. Structural representations of linear χ-MrIA (top) and cyclic χ-MrIA (bottom).
Both the peptides have very similar structures. The β-sheets are in blue, the loop and turn regions are in purple. The residues used to link N and C-termini of χ-MrIA are labeled and highlighted in orange. The disulfide bonds in green are shown in a ball-and-stick representation. The structures were visualized using PyMol.
Figure 8
Figure 8. Structures and electrostatic surfaces of ω-conotoxins.
Important residues identified through SAR studies are indicated on the left panels. ω-MVIIA, ω-MVIIC and ω-GVIA target mammalian voltage-gated calcium channels, whereas ω-TxVIIA is a mollusc-selective toxin. Obvious differences in electrostatic potentials likely account for the different pharmacologies.
Figure 9
Figure 9. Structures and electrostatic surfaces of μ-conotoxins.
Important residues identified through SAR studies are indicated on the left panels. μ-SmIIIA, μ-GIIIA, μ-PIIIA and μ-TIIIA target Nav1.4 > Nav1.2 mammalian voltage-gated calcium channels, whereas μ-SIIIA and μ-KIIIA have shorter sequences and display a reverse selectivity (Nav1.2> Nav1.4).
Figure 10
Figure 10. 4Å resolution structure of torpedo acetylcholine receptor (left) and crystal structure of AChBP, which is homologues to the extracellular nAChR domain (right).
Left: 4Å resolution structure of torpedo acetylcholine receptor showing the extracellular, transmembrane and intracellular domains. The receptor is made of five subunits (each subunit is shown in a different color). Right: 2.2Å resolution crystal structure of AChBP, which is homologues to the extracellular (ligand binding) nAChR domain. This protein is a pentamer with five identical subunits surrounding the channel pore. The β-sheets are shown in green and α-helices in pink.
Figure 11
Figure 11. Structures and electrostatic surfaces of muscle α-conotoxins.
Important residues identified through SAR studies are indicated on the left panels. α-GI, α-SI and α-CnIA target muscle nicotinic receptors.
Figure 12
Figure 12. Structures and electrostatic surfaces of neuronal α-conotoxins.
Important residues identified through SAR studies are indicated on the left panels. 4/7 Conotoxins α-A10L-TxIA, α-PnIB, α-MII and α-Vc1.1 target AChBP, α7, α3β2 and α9α10 nAChRs, whereas 4/3 conotoxins α-ImI and α-RgIA target α3β2 and α9α10 nAChRs, respectively.
Figure 13
Figure 13. Structures and electrostatic surfaces of nAChR subtypes.
Top left panel shows the “lock and key” mechanism of interaction as seen in the α-A10L-TxIA / AChBP complex. Top right panel emphasises on the principal and complementary subunits, between which conotoxins need to fit. Bottom panel compares the molecular surfaces of the binding site in AChBP, α7, α3β2, α9α10 and muscle nAChRs.
Scheme 1
Scheme 1
A Regioselective off-resin folding strategy for the synthesis of α-GI using S-Acm in combination with the acid-labile S-Meb protecting group by Boc chemistry. B Semi-directed off-resin folding strategy for the synthesis of ω-MVIID using S-Acm in combination with the acid-labile S-Trt protecting group by Fmoc chemistry. C Regioselective off-resin folding strategy for the synthesis of ω-MVIIA using S-Acm in combination with an acid-labile S-Trt and S-Mob protecting groups by Fmoc chemistry.
Scheme 2
Scheme 2
A Regioselective off-resin folding strategy for Fmoc chemistry of α-SI and α-GI using S-tBu and S-Meb with one-pot disulfide formation at different temperatures., B Off-resin folding strategies of α-GI using S-tBu and S-Acm groups. C Unsuccessful regioselective off-resin folding strategy for α-GI trying to exploit the S-tBu stability to iodine.
Scheme 3
Scheme 3. Regioselective off-resin folding strategy for the synthesis of an α-SI dimer by Fmoc chemistry utilizing S(tBu), S(Trt), S(Meb) and S(Acm) for orthogonal disulfide bond formation.
Scheme 4
Scheme 4
A Regioselective on-resin folding strategy using S-Fm in combination with S-Acm for the synthesis of α-GI by Boc-SPPS. B and C Regioselective on-resin folding strategy for α-SI employing the S(Tmob) and S(Xan) groups in combination with the S(Acm) protecting group.,
See this image and copyright information in PMC

References

    1. Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Drug Discov Today. 2010;15:40. - PubMed
    1. McGee P. Drug Discovery. 2005;8
    1. Dutertre S, Lewis RJ. J Biol Chem. 2010;285:13315. - PMC - PubMed
    1. Livett BG, Gayler KR, Khalil Z. Curr Med Chem. 2004;11:1715. - PubMed
    1. Olivera BM. Annu Rev Ecol Syst. 2002;33:25.

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