Solving the α-Conotoxin Folding Problem: Efficient Selenium-Directed On-Resin Generation of More Potent and Stable Nicotinic Acetylcholine Receptor Antagonists

Muttenthaler, Markus; Nevin, Simon T.; Grishin, Anton A; Ngo, Shyuan T.; Choy, P. T.; Daly, Norelle L.; Hu, Shuhong; Armishaw, Christopher J.; Wang, C-I Anderson; Lewis, Richard J.; Martin, Jennifer L.; Noakes, Peter G.; Craik, David J.; Adams, David J.; Alewood, Paul F.

doi:10.1021/ja910602h

Cited by 128 publications

(170 citation statements)

References 43 publications

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“…36 Meanwhile, researchers have investigated several toxins such as apamin and conotoxin for modification via partial or full replacement of disulfide bonds by diseleno bonds. 23,[39][40][41] The produced analogs were more stable than their native counterparts and structural analysis showed that the slightly larger atomic radius of selenium had no significant impact on the overall structure. 23 It was reported that disulfide bonds occurred in nearly 30% of proteins, 42 and many such peptides and proteins had important physiological functions.…”

Section: Discussionmentioning

confidence: 99%

“…23,[39][40][41] The produced analogs were more stable than their native counterparts and structural analysis showed that the slightly larger atomic radius of selenium had no significant impact on the overall structure. 23 It was reported that disulfide bonds occurred in nearly 30% of proteins, 42 and many such peptides and proteins had important physiological functions. As a tumor-targeting moiety, a variety of disulfide-constrained peptides exist, especially those screened by phage display, such as CSNRDARRC peptide for bladder cancer, 43 CMGNKRSAKRPC for rhabadominosarcoma, 44 and CASPSGALRSC for breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, a systematic comparison of Syp-1 versus Lyp-1 to mediate tumor-targeted In recent decades, great progress has been made in the chemistry of selenopeptide and selenoprotein, which provide a novel route for efficient preparation (total synthesis and folding), functional research, structural analysis, and even potential clinical application of peptides and proteins. 23,[36][37][38][39][40][41] For example, the potential of preformed peptidyl α-selenoesters in native chemical ligation has been explored to mediate rapid reaction at intractable sites. 36 Meanwhile, researchers have investigated several toxins such as apamin and conotoxin for modification via partial or full replacement of disulfide bonds by diseleno bonds.…”

Section: Discussionmentioning

confidence: 99%

“…Since selenium is a member of the sulfur group on the periodic table of elements, Sec has a structure similar to that of cysteine, and the replacement of disulfide bonds by diseleno bonds may only produce marginal changes in the structure of the peptide and protein. 23 In addition the higher reduction potential of Sec than cysteine can entail a remarkably enhanced stability of the diseleno linkage against reduction. 24 Even more attractive is the fact that selenium is an essential micronutrient for human health.…”

Section: Introductionmentioning

confidence: 99%

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Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide

Wang²,

Zhang³

et al. 2013

IJN

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Peptide ligands have played an important role in tumor-targeted drug delivery as targeting moieties. The in vivo fate of peptide-mediated drug delivery systems and the following antitumor effects may greatly depend on the stability of the peptide ligand. In the current study, a tumor-targeting cyclic peptide screened by phage display, Lyp-1 (a peptide that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors), was structurally modified by replacement of the original intramolecular disulfide bond with a diseleno bond. The produced analog Syp-1 (seleno derivative of Lyp-1) maintained specific binding ability to the target protein p32 (Kd = 18.54 nM), which is similar to that of Lyp-1 (Kd = 10.59 nM), indicated by surface plasmon resonance assay. Compared with Lyp-1, Syp-1 showed significantly improved stability against serum. After the peptide attached onto the surface of fluorophore-encapsulating liposomes, the more efficient tumor uptake of liposomal fluorophore mediated by Syp-1 was observed. Furthermore, Syp-1 modified liposomal doxorubicin presented the most potent tumor growth inhibitory ability among all the therapeutic groups, with a low half maximal inhibitory concentration of 588 nM against MDA-MB-435 cells in vitro and a high tumor inhibition rate of 73.5% in vivo. These findings clearly indicated that Syp-1 was a stable and effective tumor targeting ligand and suggest that the sulfur-to-selenium replacement strategy may help stabilize the phage-displayed cyclic peptide containing disulfide-bond under physiological conditions and strongly support the validity of peptide-mediated drug targeting.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide

Wang²,

Zhang³

et al. 2013

IJN

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“…Moreover, we reasoned that the relative stability of SeS-linked intermediates might play a role in the suggested biosynthetic pathway outlined in Scheme 1. Notably, the higher stability of selenenylsulfide bonds as compared to disulfides has been exploited for solving peptide-folding problems and in protein engineering; [54,55] in addition to the favorable formation of SeS over S 2 , [56] the former possesses a lower redox potential (typically 70 mV lower than the corresponding disulfides). [19] Glutathionyl-sugar conjugates 4 and 5, and glycoprotein SBL-C156-SSe-Glc 8 c were incubated in rat plasma.…”

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confidence: 99%

Selenenylsulfide‐Linked Homogeneous Glycopeptides and Glycoproteins: Synthesis of Human “Hepatic Se Metabolite A”

et al. 2011

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Selenium is a critical mammalian trace element found in proteins in the form of selenocysteine (SeCys) or selenomethionine (SeMet), but its role and metabolism are only partially understood. [1][2][3] Early studies [1,2] have surprisingly shown excretion of selenium as selenosugar 1, so-called "hepatic Se metabolite B"; its presence in rats and humans (liver and urine) also suggests a common cross-species excretion mechanism (Scheme 1). These studies implicated 4, so-called "hepatic Se metabolite A", which was neither isolated in pure form nor fully characterized, as the precursor on the basis of MS fragmentation. Selenosugars 2 and 3 have also been detected in urine, but, notably, glutathionyl precursors (e.g., 5) of these trace metabolites have not yet been identified.[3] Indeed, the exact mechanism of selenium metabolism remains unclear, as do the roles of 4 and 5, and the need for authentic standards has recently been emphasized.

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The Chemistry of Selenocysteine

Metanis¹,

Beld²,

Hilvert³

2011

Patai's Chemistry of Functional Groups

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Selenocysteine is a redox active amino acid. It is inserted co‐translationally into a number of natural proteins, providing them with a range of interesting enzymatic activities; it can also be incorporated into artificial peptides and proteins as a structural and mechanistic probe. In this chapter, the chemistry and biochemistry of this novel amino acid is reviewed. In addition to the (bio)synthesis of selenocysteine, selenopeptides and selenoproteins, the roles selenium plays in enzyme catalysis and its utility for diverse biotechnological applications are discussed.

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Solving the α-Conotoxin Folding Problem: Efficient Selenium-Directed On-Resin Generation of More Potent and Stable Nicotinic Acetylcholine Receptor Antagonists

Cited by 128 publications

References 43 publications

Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide

Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide

Selenenylsulfide‐Linked Homogeneous Glycopeptides and Glycoproteins: Synthesis of Human “Hepatic Se Metabolite A”

The Chemistry of Selenocysteine

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