Peptide Modifications: Linkers, Spacers and PEGylation

PEGylation is the process of covalently attaching polyethylene glycol (PEG) polymer chains to peptides or proteins. By increasing their molecular mass and shielding them from proteolytic enzymes, PEGylation improves the pharmacokinetics of both peptides and proteins. PEGylation reduces renal clearance and results in more sustained absorption after subcutaneous administration, as well as restricted distribution.

Pharmacological advantages of PEGylation:

• Improved drug solubility and enhanced protection from proteolytic degradation. The PEG polymer, along with its associated water molecules, acts like a shield to protect the attached drug from enzyme degradation, thereby limiting adverse immunological effects. PEGylated drugs are more stable over a range of pH and temperature changes compared with their unPEGylated counterparts.
• Reduced dosing frequency with potentially reduced toxicity. PEG exhibits little toxicity, and is eliminated intact from the body by either the kidneys (for PEGylated drugs <30 kDa) or in the feces (for PEGylated drugs >20 kDa).
• Increased drug stability and extended circulating life. PEG lacks immunogenicity, and antibodies against PEG in rabbits are generated only if it is combined with highly immunogenic proteins.

LifeTein can attach the mini-PEGs to peptides. Some examples are listed below:

• {Gly}, 2 Carbons
• {Beta-Ala}, 3 Carbons
• {GABA}, 4 Carbons
• {Ava}, 5 Carbons
• {AEA}, Aminoethoxyacetic Acid
• {ANP Linker}
• {Ahx}, 6 Carbons:
• Fmoc-ε-Ahx-OH, or N-ε-Fmoc-ε-aminocaproic acid; or Fmoc-6-aminohexanoic acid; CAS number: 88574-06-5; Molecular weight: 353.42 g/mol.
• Synthesis using an Ahx linker in the lysine core resulted in better yields. Ahx increases the flexibility of peptide chains, which might help keep peptide chains properly solvated during synthesis, thereby preventing aggregation and increasing the amount of viable growing peptide sequences
• Ahx or b-Ala can be used successfully as spacers during the generation of FITC-labeled peptides, which increases the stability of the fluorescent label. FITC can also be linked easily to a cysteine thiol moiety or to the amino group of lysine at any position.



• {Mini-PEG}, 9 Carbons, CAS number: 166108-71-0; Fmoc-NH-(PEG)-COOH, or Fmoc-8-amino-3,6-dioxaoctanoic acid; Molecular weight: 385.42 g/mol; C21H23NO6




• {Mini-PEG2}, 13 Carbons, CAS number: 867062-95-1; Fmoc-NH-(PEG)2-COOH, or Fmoc-12-amino-4,7,10-trioxadodecanoic acid; Molecular weight: 443.5 g/mol; C24H29NO7




• {Mini-PEG3}, 16 Carbons, CAS number: 557756-85-1; Fmoc-NH-(PEG)3-COOH, or Fmoc-15-amino-4,7,10,13-tetraoxapentadecanoic acid; Molecular weight: 489.57 g/mol; C26H35NO8

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