Peptide chemistry toolbox for peptide therapeutics

Peptides are suitable for targeting protein-protein interactions and using as smart delivery systems for targeting to cancer cells. The main drawbacks of peptides are their susceptibility to enzymatic degradation and rapid kidney clearance. So, it is crucial to stabilizing the peptides with unnatural modifications such as modifications of the peptide backbone, lipidation, attaching polymers or modulating the primary, secondary, tertiary or quaternary structure.

The peptide backbone can be modified for facilitating the peptide synthesis, increasing their solubility, and improving the pharmacological and pharmacokinetic properties. Many building blocks such as pseudoproline dipeptides are efficient tools for disrupting secondary structures. In peptide chemistry, some common practices are used for decreasing fragility of peptides such as D-amino acids, azapeptides, methylation, backbone cyclization or secondary structure constraints. This unnatural modification has a significant impact on the extended response and stability to peptides.

Lipidation using Cholesterol, fatty acid, or palmitic acid is a modification used for transforming peptides to peptide therapeutics. Lipids conjugated to peptides will increase their half-life by stabilizing their structure or binding to the cell membrane. The most prominent lipidated peptide drugs are insulin derivatives and glucagon-like peptide-1 (GLP-1) receptor agonists: liraglutide (Victoza). The combination of PEGylation and cholesterylation has been used for developing anticancer delivery systems to increase the antiviral potency of peptides and to boost their half-life in vivo.

The introduction of differently sized polymers such as the amphiphilic polyethylene glycol (PEG) is a highly popular tool in peptide chemistry. Each oxygen atom in a PEG polymer can bind two to three molecules of water, thus significantly increase the size and solubility of the peptide attached to it. The PEGylated peptides have increased peptide solubility, lower immune response, and increased peptide bioavailability. There are fifteen PEGylated peptide drugs approved by the FDA.

Tumor antigenic peptide
Tumor Antigenic Peptides