Cyclopeptides play crucial roles in nature, serving important functions across various organisms. In plants, fungi, and bacteria, they often act as defense mechanisms, while in animals, they can function as hormone signals. Interestingly, cyclopeptides are more common in our everyday lives than many realize. For instance, microcystins, a group of cyclic peptides produced by cyanobacteria in freshwater, can be harmful to animals, including humans. On the other hand, nisin, a pentacyclic peptide, is widely used as a preservative in processed foods like cheeses, meats, canned goods, and beverages due to its ability to inhibit the growth of gram-positive bacteria. This peptide, produced by the bacteria Lactococcus lactis, is regularly consumed unknowingly by many people.
Nature is indeed a treasure trove of cyclopeptides, showcasing a wide array of chemical structures and biological activities. For example, microcystin-LR, produced by cyanobacteria, is toxic to many animals, while nisin, used in food preservation, is beneficial. Another fascinating example is the sunflower trypsin inhibitor (SFTI), a bicyclic peptide found in sunflower seeds that features a complex structure formed by connecting its N- and C-terminus via an amide bond, along with a disulfide bridge between cysteine residues. Similarly, cyclotides, such as kalata B1 found in plants, are known for their stability and resistance to heat, pH changes, and enzymatic degradation. Kalata B1, for instance, is used traditionally in Africa to induce labor, showcasing the diverse and potent nature of cyclopeptides.
These naturally occurring cyclopeptides are not just of academic interest; many have significant therapeutic applications. Notable examples include oxytocin, vancomycin, and cyclosporine, all of which are essential medicines according to the World Health Organization. Oxytocin, for instance, is widely used to induce labor or reduce postpartum bleeding. Vancomycin is a crucial antibiotic used to treat severe bacterial infections, while cyclosporine is a vital immunosuppressant used in organ transplants.
Cyclopeptide hormones have been pivotal in medicine, particularly for regulating various body functions. Synthetic versions of these hormones are often used to treat conditions where the body’s natural hormone production is insufficient. Oxytocin and vasopressin were among the first cyclic peptide hormones introduced in the 1960s. Both are nonapeptides featuring a six-amino-acid ring closed by a disulfide bridge. Oxytocin is widely used to manage labor contractions and reduce postpartum bleeding, making it one of the most commonly administered cyclopeptides. The adaptability of peptides has also allowed for the creation of analogs with enhanced activity, specificity, and stability. For example, the synthetic analog desmopressin, derived from vasopressin, is widely used to treat conditions like diabetes insipidus due to its improved stability.
Similarly, somatostatin, another cyclic peptide hormone, has been modified to produce the drug octreotide, which is used to inhibit the release of various other hormones. Octreotide and its analogs, lanreotide and pasireotide, have become significant in treating hormone-related conditions, with octreotide achieving blockbuster drug status.
Recent advancements include cyclopeptide drugs like bremelanotide and setmelanotide, approved in 2019 and 2020 respectively, for treating hypoactive sexual desire and genetic obesity. These drugs are based on natural human peptide hormones that were cyclized to enhance stability and effectiveness.
Cyclopeptides have also been invaluable in the fight against infectious diseases. Over millions of years, microorganisms have evolved cyclopeptides with potent antimicrobial properties. These natural compounds have been honed through evolution to effectively combat bacteria, fungi, and other microorganisms.
Vancomycin is one of the most well-known cyclopeptide antibiotics, used to treat severe gram-positive bacterial infections. Its derivatives, such as telavancin, dalbavancin, and oritavancin, have been developed to offer different pharmacological effects and improved activity against resistant bacterial strains. Another example is daptomycin, a cyclic lipopeptide used against gram-positive bacteria, while polymyxin B and colistin are cyclopeptides used against gram-negative bacteria, disrupting bacterial membranes to cause cell leakage.
In the realm of antifungal treatments, cyclopeptides like caspofungin, micafungin, and anidulafungin have been developed to combat yeast infections. These drugs, part of the echinocandin class, inhibit a crucial enzyme needed for fungal cell wall synthesis, effectively treating infections caused by Candida species.
In conclusion, the exploration and application of cyclopeptides from nature continue to offer remarkable benefits in various fields, particularly in medicine. These complex molecules not only exhibit unique and potent biological activities but also provide a foundation for developing new therapies that address critical health challenges.