Monthly Archives: January 2019

Peptide Synthesis Glycosylation as Biomarkers

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Glycosylation is the most abundant polypeptide chain modification in nature. Glycoproteins are a significant class of current therapeutic targets and clinical biomarkers.

Glycans can be covalently attached to the amide nitrogen of Asn residues (N-glycosylation), to the hydroxyl oxygen of Ser or Thr residues (O-glycosylation), and the indole C2 carbon of Trp through a C–C linkage (C-mannosylation).

O-linked serine and threonine glycosides and N-linked asparagine glycosides in protein glycosylation.

Glycosylation of peptides is a promising strategy for modulating the physicochemical properties of peptide drugs and for improving their absorption through biological membranes. The glycosylated peptide can target specific organs, enhance the biodistribution in tissues, improve penetration through biological membranes, increase metabolic stability and lower the clearance rate, receptor-binding, protect amino acid’s side chain from oxidation, and maintain and stabilize the physical properties of peptides, such as precipitation, aggregation and thermal and kinetic denaturation.

LifeTein provides the synthesis of glycoconjugates and the development of glycosylated peptide therapeutics. We have developed the glycosylated amino acids, which are compatible with standard protocols in Fmoc solid phase peptide synthesis. The pre-synthesized glycosylated amino acid is coupled to the elongating peptide using solid phase peptide synthesis (SPPS) in a stepwise fashion. Our typical synthesis is for the peptide of 10-20 amino acids. The integration of long peptides with more than 50 residues is difficult by stepwise synthesis, due to the incomplete couplings and epimerization.

An example of the solid-phase synthesis of glycopeptide.

The modification of peptides with different sugar entities, such as mannose, galactose, and N-acetylgalactosamine (GalNAc), exerts diverse impacts on the conformational properties of the polypeptide chain. The position of the glycosyl unit in the peptide’s structure is an essential factor in changing the conformation of the peptide backbone and may affect the biological properties of the modified peptide. LifeTein is willing to work with you on the development of therapeutic peptides using different glycosylation strategies. For example, the improved permeability and higher metabolic stability of the glycosylated neuropeptides resulted in a significant increase in their bioavailability, which might account for the enhanced analgesic effect of the glycopeptides.

LifeTein’s technology will help your development of carbohydrate-modified peptide drugs.

Name CAS Formula
Fmoc-L-Ser((Ac)3-β-D-GlcNAc)-OH 160067-63-0 C32H36N2O13
Fmoc-L-Thr((Ac)3-β-D-GlcNAc)-OH 160168-40-1 C33H38N2O13
FMoc-Asn(β-D-GlcNAc(Ac)3)-OH 131287-39-3 C33H37N3O13
beta-D-Glucose pentaacetate 604-69-3 C16H22O11
Gluconic acid 526-95-4 C6H12O7
6-phosphogluconic acid 921-62-0 C6H13O10P
2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate 14152-97-7 C15H19NO9S
Name CAS Formula
Fmoc-L-Ser((Ac)3-β-D-GalNAc)-OH 1676104-71-4 C32H36N2O13
Fmoc-L-Ser((Ac)3-α-D-GalNAc)-OH 120173-57-1 C32H36N2O13
Fmoc-Thr(GalNAc(Ac)3-α-D)-OH 116783-35-8 C33H38N2O13
Fmoc-L-Thr(β-D-GalNAc(Ac)3)-OH 133575-43-6 C33H38N2O13
beta-D-Galactose pentaacetate 4163-60-4 C16H22O11
1,2,3,4,6-Penta-O-acetyl-α-D-galactopyranose  4163-59-1 C16H22O11
Name CAS Formula
Fmoc-L-Ser(ManNAc)-OH    
Fmoc-Thr(ManNAc)-OH    
α-D-MANNOSE PENTAACETATE 4163-65-9 C16H22O11
D-MANNOSE PENTAACETATE 25941-03-1 C16H22O11
D-Mannopyranose tetraacetate 140147-37-1 C14H20O10

Strategies for peptide macrocyclization: head to tail cyclization

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Head to tail cyclized for the improved half-life and permeability

Various modifications have been incorporated in the peptides such as acetylation, amidation, cyclization, PEGylation, glycosylation, succinylation, and hydroxylation, to increase the half-life of peptides.

Bioactive head-to-tail cyclic peptides are promising lead structures for the development of new pharmaceuticals with their high selectivity, potency, and improved enzymatic stability.

Cyclic peptides are usually synthesized with an N-terminal amide linkage that closes the ring structure with a C-terminal carboxylic acid. The current methods for amide formation are expensive and inelegant as the top challenge for organic chemistry. The issues of waste and expense associated with amide formation are responsible for the enormous cost of commercial therapeutic peptides. The reaction typically renders a very low yield.

Recently, LifeTein developed a single-step preparation of the amide cyclization with a high yield. The resulting peptide macrocycles are conformationally stable with multiple intramolecular hydrogen bonds. LifeTein’s advances in amide-forming methodologies can have far-reaching impacts across scientific disciplines. The unnatural amino acids can be easily incorporated during the synthesis for stability or enhanced activity, or specific probes for interrogating binding and biological function during the synthesis. The improved amide-forming chemical reactions will not damage the structure of any unnatural amino acids.

This cyclization method allows us to synthesize complex, highly functionalized amide-based structures without the need for aggressive reactants, expensive protecting groups and longer reaction times.