Modifying Peptides

peptide drugs
Photo: University of Copenhagen

Small proteins with great potential

While peptides are small proteins with great therapeutic potential, they display several inherent weaknesses as candidates. First, many peptides are broken down in the intestinal system before they can enter the rest of the body.

Second, those peptides that are not broken down have difficulty passing through the intestinal wall to enter the bloodstream. Compounds have to enter the bloodstream in order to be transported to the part of the body where they are intended to act. 

And finally, those peptides that do enter the bloodstream are broken down very quickly. Typically half of a given peptide will be inactive after five minutes.

peptide metabolism

The problem of poor absorption

These problems result overall in poor absorption by the organism so that the peptide must be given often and in large doses, because there has to be a certain concentration in the blood to give any effect.

Solving these problems is an important part of the work of medicinal chemists to find new drugs based on peptides. The peptides break down rapidly because the intestine contains many digestive enzymes designed to break down proteins and peptides in food, such as meat, for example.

If the peptide drug is identical to natural peptides, the intestinal enzymes cannot tell the difference between a beefsteak and a peptide designed as a drug.

Modifying the molecular structure

Modification of the molecular structure enables the peptide to withstand the digestive enzymes. Generally speaking, peptidomimetics have greater stability against enzymatic attack. A peptidomimetic resembles a natural peptide, but instead of the usual amino acid building block, it contains either modified amino acids, unnatural amino acids or other synthetic building blocks designed to reduce peptide breakdown.