Glycosylation of Conotoxins

Gerwig, Gerrit J.; Hocking, Henry G.; Stöcklin, Reto; Kamerling, Johannis P.; Boelens, Rolf

doi:10.3390/md11030623

Cited by 26 publications

(21 citation statements)

References 88 publications

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“…The best characterized of these AMPs is styelin D, which possesses α-helical structure and is highly unusual in that it contains twelve post-translationally modified residues [77]. For example, the peptide contained multiple bromotryptophan residues, which are found in the AMPs of other marine organisms [218,219,220,221,222] and play an important role in the life of sea sponges and lower marine invertebrates [223]. Styelin D’s post-translationally modified residues enhanced the peptide’s membranolytic action at low pH but only against Gram-positive bacteria.…”

Section: An Overview Of Ph Dependent Peptides and Proteins With Anmentioning

confidence: 99%

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

et al. 2016

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Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel delivery systems. Nonetheless, many pH dependent AMPs and antimicrobial proteins have yet to be fully characterized and these molecules, as a whole, represent an untapped source of novel biologically active agents that could aid fulfillment of the urgent need for alternatives to conventional antibiotics, helping to avert a return to the pre-antibiotic era.

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Section: An Overview Of Ph Dependent Peptides and Proteins With Anmentioning

confidence: 99%

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

et al. 2016

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“…[20] Nevertheless,s nake toxins are predominantly reported to possess N-linked glycosylation, especially serine proteases,w here the glycan may modulate the protease catalytic activity. [22] Then onglycosylated (TcNPa-ng) and glycosylated (TcNPa) peptides were synthesized using standard Fmoc solid-phase peptide synthesis on Fmoc-serine-Wang resin (see Figure S3 in the Supporting Information). The glycan, Gal-GalNAc,i sl inked to inhibiting proteolytic degradation and gave two orders of magnitude greater potencya sa na nalgesic than the nonglycosylated form.…”

Section: Methodsmentioning

confidence: 99%

“…The glycan, Gal-GalNAc,i sl inked to inhibiting proteolytic degradation and gave two orders of magnitude greater potencya sa na nalgesic than the nonglycosylated form. [22] Then onglycosylated (TcNPa-ng) and glycosylated (TcNPa) peptides were synthesized using standard Fmoc solid-phase peptide synthesis on Fmoc-serine-Wang resin (see Figure S3 in the Supporting Information). Evaluation of their secondary structures was undertaken by circular dichroism (CD) analysis in 50 %T FE/H 2 Oa nd 50 %H FIP/H 2 O.…”

Section: Methodsmentioning

confidence: 99%

A Defined α‐Helix in the Bifunctional O‐Glycosylated Natriuretic Peptide TcNPa from the Venom of Tropidechis carinatus

et al. 2015

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Natriuretic peptides (NP) play important roles in human cardiac physiology through their guanylyl cyclase receptors NPR-A and NPR-B. Described herein is a bifunctional O-glycosylated natriuretic peptide, TcNPa, from Tropidechis carinatus venom and it unusually targets both NPR-A and NPR-B. Characterization using specific glycosidases and ETD-MS identified the glycan as galactosyl-β(1-3)-N-acetylgalactosamine (Gal-GalNAc) and was α-linked to the C-terminal threonine residue. TcNPa contains the characteristic NP 17-membered disulfide ring with conserved phenylalanine and arginine residues. Both glycosylated and nonglycosylated forms were synthesized by Fmoc solid-phase peptide synthesis and NMR analysis identified an α-helix within the disulfide ring containing the putative pharmacophore for NPR-A. Surprisingly, both forms activated NPR-A and NPR-B and were relatively resistant towards proteolytic degradation in plasma. This work will underpin the future development of bifunctional NP peptide mimetics.

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“…Finally, it is worth noting that some animals use glycosylated, neurotoxic peptides as a self-defense mechanism. Many cone snails use a glycosylated conotoxins to paralyze attackers (Gerwig et al, 2013 ). Olivera and coworkers (Craig et al, 1999 ), among others, synthesized non-glycosylated versions of a number of these peptides, and found that although the non-glycosylated versions showed improved neurotensin receptor binding affinity compared with the native, glycosylated peptides, the native peptides still showed a greater than 10-fold increase in i.v .…”

Section: Benefits and Disadvantages Of Carbohydrate Incorporationmentioning

confidence: 99%

CNS active O-linked glycopeptides

Jones

Polt

2015

Front. Chem.

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Naturally occurring glycopeptides and glycoproteins play important roles in biological processes. Glycosylation is one of the most common post-translational modifications in vivo. Glycopeptides are involved in cell signaling and sorting, providing cell surface markers for recognition. From the drug design and synthesis perspective, modification of a peptide through glycosylation results in increased bioavailability and bioactivity of glycopeptides in living systems with negligible toxicity of degradation products. Glycopeptide synthesis can be accomplished through incorporation of a glycosylated amino acid in solid phase peptide synthesis (SPPS) to form the desired peptide, or via incorporation of sugar-amino acid moieties. Additionally, research indicates that glycosylation increases penetration of the blood-brain barrier (BBB) by peptides, which may lead to novel therapeutics for neurological disorders. Recent applications of glycopeptides have focused on the in vivo central nervous system (CNS) effects after peripheral administration of centrally active peptides modified with various carbohydrates.

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Glycosylation of Conotoxins

Cited by 26 publications

References 88 publications

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

A Defined α‐Helix in the Bifunctional O‐Glycosylated Natriuretic Peptide TcNPa from the Venom of Tropidechis carinatus

CNS active O-linked glycopeptides

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