Peptidomimetics mimic biologically active peptides but have structural differences that make them more stable and available to target receptors. They can influence cellular activities and are attractive targets for drugs. Modifications can improve stability, binding site fit, and transport across biological membranes. Peptidomimetics have been successful in identifying new active compounds, including drugs for high blood pressure and cancer. Combinatorial chemistry can be used to synthesize large libraries of compounds for screening. The field of peptidomimetic design is growing due to its frequent benefits.
A peptidomimetic is a compound designed to mimic a biologically active peptide, but has structural differences that give greater advantages to its function as a drug. For example, a peptidomimetic designed to mimic a hormone would have greater stability and be more available for its target receptor to transmit signals. A peptide is a large molecule made up 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 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 influence a wide range of cellular activities, including digestion, reproduction and pain sensitivity. Many peptide activities are attractive as targets for drugs, but it can be difficult for them to cross the membrane to enter a cell. Furthermore, the peptides that make it into a cell are often unstable.
Peptidomimetics were initially designed to limit the conformational mobility of the peptide, in other words, the degree to which it can bend. Having the peptides fixed in place makes them more likely to react with the desired target and limits unwanted side effects. Another goal is to increase their stability. The incorporation of non-natural compounds into their backbone makes these new compounds much less likely to be degraded by enzymes that break down peptides and peptidomimetics.
Peptides consist of chains of amino acids linked by a peptide bond between the carboxyl terminus of one amino acid and the amino terminus of the next. There are numerous ways in which peptidomimetics can be modified. A peptidomimetic can have the peptide bond completely displaced, replacing it with beta amino acids, which contain two extra carbon atoms between the amino and carboxyl terminus of two adjacent amino acids. This can give rise to a wide range of biologically active and break-resistant configurations.
Organic chemists have identified many other ways to replace the peptide bond. Additionally, the side chains are often altered, sometimes by the addition of cyclic peptides. These are peptides in which the amino terminus and the carboxyl terminus of the same molecule are connected. All of these changes are generally designed to improve the stability of the peptidomimetic.
Other factors to consider when synthesizing peptidomimemetics are optimal binding site fit and whether to make strategic regions favor being in aqueous solution or in membranes. Transport across biological membranes is another factor that can be improved by the targeted synthesis of a peptidomimetic. Detailed knowledge of the target is required to make these decisions.
This approach has been very valuable in identifying new active compounds. Some successful drugs have been developed using this method, including a peptidomimetic angiotensin-converting enzyme (ACE) inhibitor, which is used to treat high blood pressure and other conditions. Other peptidomimetic inhibitors include those designed to cause cancer cells to go into programmed cell death, known as apoptosis. Several research laboratories have had success with this technique in model systems and at least one patent has been applied for in this area.
The synthesis of peptidomimetics can be designed for a specific compound or large libraries can be synthesized and screened. An example of the latter approach uses 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 spans a number of scientific disciplines. The success rate for identifying biologically active compounds from peptidomimetic compound libraries is much higher than that from screening peptide libraries. With frequent benefits of increased stability and availability to their target, the field of peptidomimetics is growing.
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