What is a Peptidomimetic?

Helga George

A peptidomimetic is a compound that is designed to mimic a biologically active peptide, but has structural differences that give greater advantages for its function as a drug. For instance, a peptidomimetic that is designed to mimic a hormone would have greater stability and be more available to its target receptor to transmit signals. A peptide is a large molecule made of amino acids that are linked with peptide bonds. Peptidomimetics may have unnatural amino acids or other unusual compounds to stabilize their structure or alter their biological activity.

The synthesis of peptidomimetics can be by design for a specific compound or large libraries can be synthesized and screened.
The synthesis of peptidomimetics can be by design for a specific compound or large libraries can be synthesized and screened.

The reason for the interest in peptides is that many have significant biological activity. This means they can act as hormones and signal molecules for the central nervous system and the immune system. Peptides can affect a wide range of cellular activity, among them digestion, reproduction, and sensitivity to pain. Many peptide activities are of interest as targets for drugs, but it can be difficult for them to cross the membrane to enter a cell. Also, peptides that do make it into a cell are frequently unstable.

Peptidomimetics were first designed to limit the conformational mobility of the peptide — in other words, the degree to which it can bend. Having peptides fixed in place makes it more likely that they will react with their desired target and limits undesirable side effects. Another goal is to increase their stability. The incorporation of unnatural compounds into their backbone makes it much less likely that these novel compounds will be degraded by the enzymes that break down peptides and peptidomimetics.

Peptides are comprised of chains of amino acids connected by a peptide bond between the carboxy terminus of one amino acid and the amino terminus of the next. There are numerous ways in which peptidomimetics can be altered. A peptidomimetic may have the peptide bond displaced entirely, replacing it with beta amino acids, which contain two extra carbon atoms between the amino and carboxy terminus of two adjacent amino acids. This can give rise to a wide array of configurations that are biologically-active and resistant to breakdown.

Organic chemists have identified many other ways of replacing the peptide bond. In addition, side chains are often altered, sometimes by the addition of cyclic peptides. These are peptides in which the amino terminus and the carboxy terminus of the same molecule are linked. All of these changes are usually designed to enhance the stability of the peptidomimetic.

Other factors to consider when synthesizing peptidomimemetics are the optimal fit of the binding site and whether to make strategic regions favor being in aqueous solution or in membranes. Transport across biological membranes is yet another factor that can be improved by the targeted synthesis of a peptidomimetic. A detailed knowledge of the target is required to make these decisions.

This approach has been highly valuable for identifying new active compounds. Some successful drugs have been developed using this method, including a peptidomimetic inhibitor of angiotensin-converting enzyme (ACE), which is used to treat high blood pressure and other conditions. Other peptidomimetic inhibitors include those designed to trigger cancer cells to go into programmed cell death, known as apoptosis. Several research labs have had success with this technique in model systems, and at least one patent has been applied for in this field.

The synthesis of peptidomimetics can be by design for a specific compound or large libraries can be synthesized and screened. An example of the latter approach utilizes combinatorial chemistry. This is the strategy of synthesizing a large number of molecules that are structurally related. The library of compounds produced can then be screened for active compounds.

The field of peptidomimetic design crosses a number of scientific disciplines. The success rate for identifying biologically-active compounds from libraries of peptidomimetic compounds is much higher than that from screening libraries of peptides. With the frequent advantages of increased stability and availability to their target, the field of peptidomimetics is growing.

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