Integrated development of peptides

Integrated development of peptides has a number of advantages.

Built-in advantages of peptide development

Peptides are currently gaining momentum due to their following built-in advantages :

• high activity, specificity and affinity
• small in size, ease to synthesise relative to antibodies or proteins
• ability to interact with complex receptors relative to small molecules
• ease of design and modification
• limited safety risks relative to small molecules as degradation products are mainly amino acids 
• globally less immunogenic than recombinant antibodies or proteins
• potential to penetrate the cell membranes relative to antibodies or proteins
• minimal drug-drug interaction as mainly cleared and/or degraded by peptidases

Limitations of peptide development

However, they also have limitations which can reduce their development :

• short half-life
• limited potential of non parenteral administration
• limited potential to penetrate the cell membranes relative to small molecule

Advantages of integrated development of peptides

The last decades have generated major improvements that increase markedly the attractiveness and peptides. These improvements (not excluding each other) should be integrated during the development of peptides. Examples include:

Marked improvements in half-life by lateral structural modifications:

• Lipidation: the lipid chain(s) increase their affinity for albumin leading to reduced excretion of the complex. Moreover, the peptide may be partially protected from peptidases by steric hindrance. Examples: liraglutide, semaglutide.
• Peptide side-chain: reduced excretion by an increase of apparent volume. In addition, the peptide side-chain may facilitate cell penetration and blood-brain barrier crossing.
• Pegylation: reduced excretion through increase of apparent volume. Pegylation can, however, be complex and costly.

Marked post-hoc improvements in half-life by slow-release formulation.

Marked improvements in cell penetration:

• For instance with the addition of a TAT chain.

Marked improvements in stability:

• Substitution of labile amino acids.
• Partial or total (mainly retro-inverso) substitution with dextrogyre amino-acids less sensitive to peptidases.

For more information on integrated development of peptides please contact COPEXIS today.